Triazole compounds useful in therapy

ABSTRACT

A compound of formula (I),  
                 
 
     or a pharmaceutically acceptable derivative thereof, wherein  
     V represents —(CH 2 ) d (O) e —, —CO—, or —CH(C 1-6  alkyl)-;  
     W is —O—, —S(O) a —, or —N(R 1 )— 
     R 1  represents H, C 1-6  alkyl, (CH 2 ) b COR 2 , CO(CH 2 ) b NR 2 R 3 , SO 2 R 2 , (CH 2 ) c OR 2 , (CH 2 ) c NR 2 R 3 , or (CH 2 ) b het 1 ;  
     het 1  represents a saturated or unsaturated heterocycle of from 3 to 8 atoms containing one or more heteroatoms selected from O, N, or S, optionally substituted with C 1-6  alkyl;  
     X and Y independently represent H, C 1-6  alkyl, halogen, OH, CF 3 , OCF 3 , OR 4 ;  
     Z represents —(CH 2 ) f (O) g —, —CO— or —CH(C 1-6  alkyl)-;  
     Ring A represents a 4-7 membered, saturated N-containing heterocycle, optionally substituted with OH, and in which optionally at least one ring N is substituted with O;  
     Ring B represents phenyl or a 4-7 membered unsaturated N-containing heterocycle, optionally substituted with OH, halogen, CN, CONH 2 , CF 3 , OCF 3 , and in which optionally at least one ring N is substituted with O;  
     R 2  and R 3  independently represent H, C 1-6  alkyl [optionally substituted with OH, halogen, N(C 1-6  alkyl) 2 , or C 1-6  alkyloxy], C 1-6  alkyloxy, N(C 1-6  alkyl) 2 , or [C 3-8  cycloalkyl];  
     or R 2  and R 3 , together with the nitrogen atom to which they are attached independently represent a heterocycle of from 3 to 8 atoms, optionally substituted with C 1-6  alkyl;  
     R 4  represents straight or branched C 1-6  alkyl,  
     a and c independently represent 0, 1, or 2;  
     b, e and g independently represent 0 or 1;  
     d and f independently represent 1 or 2;  
     are useful in the treatment of dysmenorrhoea

[0001] This application claims priority to U.S. Provisional ApplicationSerial No. 60/455,455, filed Mar. 18, 2003, which claims priority toBritish Application Serial No. 0303852.8, filed Feb. 19, 2003.

[0002] This invention relates to novel compounds useful in therapy andto processes for the preparation of, intermediates used in thepreparation of, compositions containing and the uses of, suchderivatives.

[0003] Japanese Patent Application No. 09-328484 describes triazolequinoxalines useful as anti-allergy and anti-inflammatory agents.Japanese Patent Application No. 09-132576 describes triazolequinoxalines useful as anti-allergy and anti-inflammatory agents.Japanese Patent Application No. 06-135965 describes triazolequinoxalines useful for curing and preventing allergies, inflammationand PAF-associated diseases. Japanese Patent Application No. 06-128262describes triazole quinoxalines useful for intermediates of drugs andagrochemicals.

[0004] The compounds of the present invention have been found to haveuseful pharmaceutical properties. They may be used to treat aggression,Alzheimer's disease, anorexia nervosa, anxiety, anxiety disorder,asthma, atherosclerosis, autism, cardiovascular disease (includingangina, atherosclerosis, hypertension, heart failure, edema,hypernatremia), cataract, central nervous system disease,cerebrovascular ischemia, cirrhosis, cognitive disorder, Cushing'sdisease, depression, diabetes mellitus, dysmenorrhoea (primary andsecondary), emesis (including motion sickness), endometriosis,gastrointestinal disease, glaucoma, gynaecological disease, heartdisease, intrauterine growth retardation, inflammation (includingrheumatoid arthritis), ischemia, ischemic heart disease, lung tumor,micturition disorder, mittlesmerchz, neoplasm, nephrotoxicity,non-insulin dependent diabetes, obesity, obsessive/compulsive disorder,ocular hypertension, preclampsia, premature ejaculation, premature(preterm) labor, pulmonary disease, Raynaud's disease, renal disease,renal failure, male or female sexual dysfunction, septic shock, sleepdisorder, spinal cord injury, thrombosis, urogenital tract infection orurolithiasis.

[0005] Particularly of interest are the following diseases or disorders:

[0006] anxiety, cardiovascular disease (including angina,atherosclerosis, hypertension, heart failure, edema, hypernatremia),dysmenorrhoea (primary and secondary), endometriosis, emesis (includingmotion sickness), intrauterine growth retardation, inflammation(including rheumatoid arthritis), mittlesmerchz, preclampsia, prematureejaculation, premature (preterm) labor and Raynaud's disease.

[0007] In particular, they exhibit vasopressin antagonistic activity andcan be used in the treatment of dysmenorrhoea (primary and secondary).

[0008] There is a high unmet need in the area of menstrual disorders andit is estimated that up to 90% of all menstruating women are affected tosome degree. Up to 42% of women miss work or other activities due tomenstrual pain and it has been estimated that around 600 million workhours a year are lost in the US as a result (costing around $2 billionin lost productivity).

[0009] Menstrual pain in the lower abdomen is caused by myometrialhyperactivity and reduced uterine blood flow. These pathophysiologicalchanges result in abdominal pain that radiates out to the back and legs.This may result in women feeling nauseous, having headaches andsuffering from insomnia. This condition is called dysmenorrhoea and canbe classified as either primary or secondary dysmenorrhoea.

[0010] Primary dysmenorrhoea is diagnosed when no abnormality causingthe condition is identified. This affects up to 50% of the femalepopulation. Where an underlying gynaecological disorder is present, suchas endometriosis, pelvic inflammatory disease (PID), fibroids orcancers, secondary dysmenorrhoea will be diagnosed. Secondarydysmenorrhoea is diagnosed in only approximately 25% of women sufferingfrom dysmenorrhoea. Dysmenorrhoea can occur in conjunction withmenorrhagia, which accounts for around 12% of referrals to gynaecologyoutpatients departments.

[0011] Currently, women suffering from primary dysmenorrhoea are treatedwith non-steroidal anti-inflammatory drugs (NSAID's) or the oralcontraceptive pill. In cases of secondary dysmenorrhoea surgery may beundertaken to correct the underlying gynaecological disorder.

[0012] Women suffering from dysmenorrhoea have circulating vasopressinlevels which are greater than those observed in healthy women at thesame time of the menstrual cycle.

[0013] Inhibition of the pharmacological actions of vasopressin, at theuterine vasopressin receptor, may prevent dysmenorrhoea.

[0014] According to the present invention there is provided a compoundof formula (I),

[0015] or a pharmaceutically acceptable derivative thereof, wherein

[0016] V represents —(CH₂)_(d)(O)_(e)—, —CO—, or —CH(C₁₋₆ alkyl)-;

[0017] W is —O—, —S(O)_(a)—, or —N(R¹)—

[0018] R¹ represents H, C₁₋₆ alkyl, (CH₂)_(b)COR², CO(CH₂)_(b)NR²R³,SO₂R², (CH₂)_(c)OR², (CH₂)_(c)NR²R³, or (CH₂)_(b)het¹;

[0019] het¹ represents a saturated or unsaturated heterocycle of from 3to 8 atoms containing one or more heteroatoms selected from O, N, or S,optionally substituted with C₁₋₆ alkyl;

[0020] X and Y independently represent H, C₁₋₆ alkyl, halogen, OH, CF₃,OCF₃, OR⁴;

[0021] Z represents —(CH₂)_(f)(O)_(g)—, —CO—or —CH(C₁₋₆ alkyl)-;

[0022] Ring A represents a 4-7 membered, saturated N-containingheterocycle, optionally substituted with OH, and in which optionally atleast one ring N is substituted with O;

[0023] Ring B represents phenyl or a 4-7 membered unsaturatedN-containing heterocycle, optionally substituted with OH, halogen, CN,CONH₂, CF₃, OCF₃, and in which optionally at least one ring N issubstituted with O;

[0024] R² and R³ independently represent H, C₁₋₆ alkyl [optionallysubstituted with OH, halogen, N(C₁₋₆ alkyl)₂, or C₁₋₆ alkyloxy], C₁₋₆alkyloxy, N(C₁₋₆ alkyl)₂, or [C₃₋₈ cycloalkyl];

[0025] or R² and R³, together with the nitrogen atom to which they areattached independently represent a heterocycle of from 3 to 8 atoms,optionally substituted with C₁₋₆ alkyl;

[0026] R⁴ represents straight or branched C₁₋₆ alkyl,

[0027] a and c independently represent 0, 1, or 2;

[0028] b, e and g independently represent 0 or 1;

[0029] d and f independently represent 1 or 2.

[0030] In the above definitions, halogen means fluoro, chloro, bromo oriodo. Alkyl groups containing the requisite number of carbon atoms,except where indicated, can be unbranched or branched chain. Examplesinclude methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyland t-butyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. Examples of alkyloxy includemethoxy, ethoxy, n-propyloxy, I-propyloxy, n-butyloxy, I-butyloxy,sec-butyloxy and t-butyloxy.

[0031] Heterocycles included within the definition of “heterocycle” arepyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl,thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl,benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl andquinoxalinyl, together with partially or fully saturated versionsthereof as well as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,homopiperazinyl, oxazepanyl, and morpholinyl.

[0032] Preferred groups of compounds are those in which any one or moreof the following apply:

[0033] (i) W is NR¹;

[0034] (ii) R¹ is C₁₋₆ alkyl, and more preferably methyl, i-propyl orn-butyl;

[0035] (iii) R¹ is H;

[0036] (iv) R¹ is (CH₂)_(b)het¹;

[0037] (v) het¹ is pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl,oxazepanyl, pyrimidinyl, pyridinyl, thiazolyl, or imidazolyl,(optionally substituted with C₁₋₆ alkyl)

[0038] (vi) R¹ is CO(CH₂)_(b)NR²R³;

[0039] (vii) R² is morpholinyl or pyrimidinyl (optionally substitutedwith C₁₋₆ alkyl [optionally substituted with OH, halogen, N(C₁₋₆alkyl)₂,or C₁₋₆alkyloxy] or NMe₂).

[0040] (viii) R² and R³ together with the nitrogen to which they areattached represent morpholinyl, pyrrolidinyl, piperazinyl, azetidinyl,tetrahydropyranyl, pyrimidinyl or piperidinyl (optionally substitutedwith C₁₋₆ alkyl)

[0041] (ix) V is —(CH₂)_(d)(O)_(e)—;

[0042] (x) Z is —(CH₂)_(f)(O)_(g)—;

[0043] (xi) d is 1;

[0044] (xii) e is 0;

[0045] (xiii) f is 1;

[0046] (xiv) g is 0;

[0047] (xv) X is H;

[0048] (xvi) Y is in the 4-position of the phenylene ring (according tothe numbering of formula (I)) to which it is attached;

[0049] (xvii) Y is halogen, preferably chloro;

[0050] (xviii) Y is alkyloxy, preferably methoxy;

[0051] (xix) Y is alkyl, preferably methyl;

[0052] (xx) Y is CF₃ or OCF₃;

[0053] (xxi) Z is (CH₂)_(d)(O)_(e);

[0054] (xxii) e is 0;

[0055] (xxiii) d is 1;

[0056] (xxiv) ring A is linked to ring B via a nitrogen atom in ring A;

[0057] (xxv) ring A is piperidinyl (optionally substituted with OH, andoptionally at least one N is substituted with O);

[0058] (xxvi) ring B is pyridinyl (optionally substituted with one ormore groups selected from OH, halogen, CN, CONH₂, CF₃, OCF₃, andoptionally at least one ring N is substituted with O), preferably it is2-pyridinyl;

[0059] (xxvii) ring B is pyrimidinyl (optionally substituted with one ormore groups selected from OH, halogen, CN, CONH₂, CF₃, OCF₃, andoptionally at least one ring N is substituted with O), preferably2-pyrimidinyl;

[0060] (xxviii) n is 1;

[0061] (xxix) n is 2.

[0062] Preferred compounds according to the present invention are:

[0063]8-Chloro-5-methyl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulenetrihydrochloride;

[0064]8-Chloro-5-isopropyl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulenetrihydrochloride;

[0065]1-[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-ethanonedihydrochloride;

[0066]8-Chloro-5-methanesulfonyl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene;

[0067]8-Chloro-5-methyl-1-(1-pyrimidin-2-yl-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene;

[0068]8-Chloro-5-methanesulfonyl-1-(1-pyrimidin-2-yl-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene;

[0069]13-Chloro-8-methyl-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-2,4,5,8-tetraaza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),3,5,12,14-pentaene;

[0070]13-Chloro-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-8-oxa-2,4,5-triaza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),3,5,12,14-pentaene;

[0071]1-[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-2-dimethylamino-ethanone;

[0072][8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-morpholin-4-yl-methanone;

[0073] (+) or (−)8-Chloro-5-(4-methyl-morpholin-2-ylmethyl)-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene;

[0074]8-Chloro-5-pyrimidin-2-yl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene;

[0075] 8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-sulphonic acid dimethylamide;

[0076]8-Chloro-1-(1-pyrimidin-2-yl-piperidin-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-sulphonicacid dimethylamide;

[0077]13-Chloro-9-methyl-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-2,4,5,9-tetraaza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),3,5,12,14-pentaene; and

[0078]13-Chloro-8-methyl-3-(1-pyrimidin-2-yl-piperidin-4-yl)-2,4,5,8-tetraaza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),3,5,12,14-pentaene.

[0079] Alternatively there is provided a compound of formula (I*),

[0080] W is O, S, or NR¹

[0081] R¹ represents H, C₁₋₆ alkyl, —(CH₂)_(a)—[C₃₋₈ cycloalkyl],phenyl, benzyl, pyridyl, pyrimidyl, —COR², —CO₂R², —CO—(CH₂)_(a)—NR²R³,—SO₂R², —(CH₂)_(b)—OR², —(CH₂)_(b)—NR²R³, or a saturated heterocycle offrom 3 to 8 atoms containing one or more heteroatoms selected from O, Nand S;

[0082] X and Y independently represent H, halogen, OH, CF₃, OCF₃, R⁴,—(CH₂)_(d)—CONR⁴R⁵, —(CH₂)_(d)—CN, —(CH₂)_(d)—SO₂NR⁴R⁵,—(CH₂)_(d)—NR⁴SO₂Me, —(CH₂)_(d)—COR⁴, —(CH₂)_(d)—OCOR⁴,—(CH₂)_(d)—NHCOR⁴, —(CH₂)_(d)—NR⁴COR⁵, —(CH₂)_(d)—OR⁶ or—(CH₂)_(d)—CO₂R⁶;

[0083] Ring A represents a piperidinyl, piperazinyl, pyrrolidinyl orazetidinyl group;

[0084] Ring B represents a phenyl, pyridinyl or pyrimidinyl group(optionally substituted with one or more groups independently selectedfrom halogen, CN, CONH₂, CF₃, OCF₃, R⁷, and —(CH₂)_(f)OR⁸);

[0085] R², R³, R⁴, R⁵and R⁷ independently represent H, straight orbranched C₁₋₆ alkyl, —(CH₂)_(c)—[C₃₋₈ cycloalkyl], phenyl, benzyl,pyridyl or pyrimidyl;

[0086] or R² and R³, or R⁴ and R⁵, together with the nitrogen atom towhich they are attached independently represent a heterocycle of from 3to 8 atoms;

[0087] R⁶ and R⁸ independently represent H, straight or branched C₁₋₆alkyl, —(CH₂)_(c)—[C₃₋₈ cycloalkyl], —(CH₂)_(e)—NR⁴R⁵, —(CH₂)_(e)—OR⁴,phenyl, benzyl, pyridyl or pyrimidyl;

[0088] n=0, 1 or 2;

[0089] a, c, d and f are all independently selected from 0, 1, 2 or 3;

[0090] b and e are independently selected from 2 or 3.

[0091] Pharmaceutically acceptable derivatives of the compounds offormula (I) according to the invention include salts, solvates,complexes, polymorphs, prodrugs, stereoisomers, geometric isomers,tautomeric forms, and isotopic variations of compounds of formula (I).Preferably, pharmaceutically acceptable derivatives of compounds offormula (I) comprise salts, solvates, esters and amides of the compoundsof formula (I). More preferably, pharmaceutically acceptable derivativesof compounds of formula (I) are salts and solvates.

[0092] The pharmaceutically acceptable salts of the compounds of formula(I) include the acid addition and base salts thereof.

[0093] Suitable acid addition salts are formed from acids which formnon-toxic salts. Examples include the acetate, aspartate, benzoate,besylate, bicarbonate/carbonate, bisulphate, borate, camsylate, citrate,edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, D- and L-lactate,malate, maleate, malonate, mesylate, methylsulphate, naphthylate,2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, palmoate,phosphate, hydrogen phosphate, dihydrogen phosphate, saccharate,stearate, succinate, sulphate, D- and L-tartrate, tosylate andtrifluoroacetate salts. A particularly suitable salt is the be sylatederivative of the compounds of the present invention.

[0094] Suitable base salts are formed from bases, which form non-toxicsalts. Examples include the aluminium, arginine, benzathine, calcium,choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine,olamine, potassium, sodium, tromethamine and zinc salts.

[0095] For a review on suitable salts see Stahl and Wermuth, Handbook ofPharmaceutical Salts: Properties, Selection and Use, Wiley-VCH,Weinheim, Germany (2002).

[0096] A pharmaceutically acceptable salt of a compound of formula (I)may be readily prepared by mixing together solutions of the compound offormula (I) and the desired acid or base, as appropriate. The salt mayprecipitate from solution and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionisation in thesalt may vary from completely ionised to almost non-ionised.

[0097] The compounds of the invention may exist in both unsolvated andsolvated forms. The term “solvate” is used herein to describe amolecular complex comprising the compound of the invention and one ormore pharmaceutically acceptable solvent molecules, for example,ethanol. The term “hydrate” is employed when said solvent is water.

[0098] Included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor non-stoichiometric amounts. Also included are complexes of the drugcontaining two or more organic and/or inorganic components what may bein stoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionised, partially ionised, or non-ionised. For a review of suchcomplexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August1975).

[0099] Hereinafter all references to compounds of formula (I) andpharmaceutically acceptable derivatives include references to salts,solvates and complexes thereof and to solvates and complexes of saltsthereof.

[0100] The compounds of the invention include compounds of formula (I)as hereinbefore defined, polymorphs, prodrugs, and isomers thereof(including optical, geometric and tautomeric isomers) as hereinafterdefined and isotopically-labelled compounds of formula (I).

[0101] As stated, the invention includes all polymorphs of the compoundsof formula (I) as hereinbefore defined.

[0102] Also within the scope of the invention are so-called “prodrugs”of the compounds of formula (I). Thus certain derivatives of compoundsof formula (I) which may have little or no pharmacological activitythemselves can, when administered into or onto the body, be convertedinto compounds of formula (I) having the desired activity, for example,hydrolytic cleavage. Such derivatives are referred to as “prodrugs”.Further information on the use of prodrugs may be found in “Pro-drugs asNovel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and WStella) and “Bioreversible Carriers in Drug Design”, Pergamon Press,1987 (ed. E B Roche, American Pharmaceutical Association).

[0103] Prodrugs in accordance with the invention can, for example, beproduced by replacing appropriate functionalities present in thecompounds of formula (I) with certain moieties know to those skilled inthe art as “pro-moieties” as described, for example, in “Design ofProdrugs” by H Bundgaard (Elsevier, 1985).

[0104] Some examples of prodrugs in accordance with the inventioninclude:

[0105] (i) where the compound of formula (I) contains a carboxylic acidfunctionality (—COOH), an ester thereof, for example, replacement of thehydrogen with (C₁-C₈)alkyl;

[0106] (ii) where the compound of formula (I) contains an alcoholfunctionality (—OH), an ether thereof, for example, replacement of thehydrogen with (C₁-C₆)alkanoyloxymethyl; and

[0107] (iii) where the compound of formula (I) contains a primary orsecondary amino functionality (—NH₂ or —NHR where R≠H), an amidethereof, for example, replacement of one or both hydrogens with(C₁-C₁₀)alkanoyl.

[0108] Further examples of replacement groups in accordance with theforegoing examples and examples of other prodrug types may be found inthe aforementioned references.

[0109] Finally, certain compounds of formula (I) may themselves act asprodrugs of other compounds of formula (I).

[0110] Also within the scope of the invention are the metabolites of thecompounds of formula (I) when formed in vivo.

[0111] Compounds of formula (I) containing one or more asymmetric carbonatoms can exist as two or more stereoisomers. Where a compound offormula (I) contains an alkenyl or alkenylene group, geometric cis/trans(or Z/E) isomers are possible, and where the compound contains, forexample, a keto or oxime group or an aromatic moiety, tautomericisomerism (‘tautomerism’) may occur. It follows that a single compoundmay exhibit more than one type of isomerism.

[0112] Included within the scope of the present invention are allstereoisomers, geometric isomers and tautomeric forms of the compoundsof formula (I), including compounds exhibiting more than one type ofisomerism, and mixtures of one or more thereof. Also included are acidaddition or base salts wherein the counter ion is optically active, forexample, D-lactate or L-lysine, or racemic, for example, DL-tartrate orDL-arginine.

[0113] Cis/trans isomers may be separated by conventional techniqueswell known to those skilled in the art, for example, fractionalcrystallisation and chromatography.

[0114] Conventional techniques for the preparation/isolation ofindividual enantiomers include chiral synthesis from a suitableoptically pure precursor or resolution of the racemate (or the racemateof a salt or derivative) using, for example, chiral HPLC.

[0115] Alternatively, the racemate (or racemic precursor) may be reactedwith a suitable optically active compound, for example, an alcohol, or,in the case where the compounds of formula (I) contains an acidic orbasic moiety, an acid or base such as tartaric acid or1-phenylethylamine. The resulting diastereomeric mixture may beseparated by chromatography and/or fractional crystallisation and one orboth of the diastereomers converted to the corresponding pureenantiomer(s) by means well known to a skilled person.

[0116] Chiral compounds of the invention (and chiral precursors thereof)may be obtained in enantiomerically-enriched form using chromatography,typically HPLC, on an asymmetric resin with a mobile phase consisting ofa hydrocarbon, typically heptane or hexane, containing from 0 to 50%isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine,typically 0.1% diethylamine. Concentration of the eluate affords theenriched mixture.

[0117] Stereoisomeric conglomerates may be separated by conventionaltechniques known to those skilled in the art—see, for example,“Stereochemistry of Organic Compounds” by E L Eliel (Wiley, New York,1994).

[0118] The present invention also includes all pharmaceuticallyacceptable isotopic variations of a compound of the formula (I) one ormore atoms is replaced by atoms having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberusually found in nature.

[0119] Examples of isotopes suitable for inclusion in the compounds ofthe invention include isotopes of hydrogen such as ²H and ³H, carbonsuch as ¹¹C, ¹³C and ¹⁴C, nitrogen such as ¹³N and ¹⁵N, oxygen such as¹⁵O, ¹⁷O and ¹⁸O, phosphorus such as ³²P, sulphur such as ³⁵S, fluorinesuch as ¹⁸F, iodine such as ¹²³I and ¹²⁵I, and chlorine such as ³⁶Cl.

[0120] Certain isotopically-labelled compounds of formula (I), forexample those incorporating a radioactive isotope, are useful in drugand/or substrate tissue distribution studies. The radioactive isotopestritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful forthis purpose in view of their ease of incorporation and ready means ofdetection.

[0121] Substitution with heavier isotopes such as deuterium, i.e. ²H,may afford certain therapeutic advantages resulting from greatermetabolic stability, for example, increased in vivo half-life or reduceddosage requirements, and hence may be preferred in some circumstances.

[0122] Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F,¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studiesfor examining substrate receptor occupancy.

[0123] Isotopically-labelled compounds of formula (I) can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described in the accompanying Examplesand Preparations using appropriate isotopically-labelled reagents inplace of the non-labelled reagent previously employed.

[0124] Pharmaceutically acceptable solvates in accordance with theinvention include those wherein the solvent of crystallisation may beisotopically substituted, e.g. D₂O, d₆-acetone and d₆-DMSO.

[0125] According to the present invention there is also provided aprocess for the production of a compound of formula (I), whichcomprises:

[0126] a) reacting a compound of formula (II) with an acid catalyst

[0127] wherein rings A and B, and groups V, W, X, Y, Z and n are asdefined above;

[0128] b) reacting a compound of formula (III)

[0129] with a compound of formula (IV)

[0130] wherein rings A and B, and groups V, W, X, Y, Z and n are asdefined above, and Z′ represents a leaving group such as halogen;

[0131] c) when W in compound (I) represents NR¹, reacting a compound offormula (V)

[0132] with a compound of formula (VI)

[0133] wherein rings A and B, and groups R¹, V, X, Y, Z and n are asdefined above, and Z″ represents a leaving group such as halogen; or

[0134] d) when W in compound (I) represents NR¹, reacting a compound offormula (V)

[0135] with a compound of formula (VII)

[0136] wherein rings A and B, and groups R¹, V, X, Y, Z and n are asdefined above;

[0137] e) reacting a compound of formula (XIII)

[0138] with a compound of formula (XXIV)

[0139] wherein rings A and B, and groups V, W, X, Y and Z are as definedabove;

[0140] f) reacting a compound of formula (XIII)

[0141] with a compound of formula (XXV)

[0142] wherein rings A and B, and groups V, W, X, Y and Z are as definedabove.

[0143] Unless otherwise provided herein:

[0144] WSCDI means 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride;

[0145] DCC means N,N′-dicyclohexylcarbodiimide;

[0146] HOAT means 1-hydroxy-7-azabenzotriazole;

[0147] HOBT means 1-hydroxybenzotriazole hydrate;

[0148] PyBOP® means Benzotriazol-1-yloxytris(pyrrolidino)phosphoniumhexafluorophosphate;

[0149] PyBrOP® means bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate;

[0150] HBTU means O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate.

[0151] Mukaiyama's reagent means 2-chloro-1-methylpyridinium iodide;

[0152] KHMDS means potassium bis(trimethylsilyl)amide;

[0153] Hünig's base means N-ethyldiisopropylamine;

[0154] Et₃N means triethylamine;

[0155] NMM means N-methylmorpholine;

[0156] HMDS means hexamethyldisilazane BINAP means2,2′-bis(diphenylphosphino)-1,1′-binaphthyl;

[0157] Dba means dibenzylideneacetone;

[0158] Boc means tert-butoxycarbonyl;

[0159] CBz means benzyloxycarbonyl;

[0160] p-TSA means p-toluenesulphonic acid

[0161] TBAF means tetra-butyl ammonium fluoride

[0162] MeOH means methanol, EtOH means ethanol, and EtOAc means ethylacetate;

[0163] THF means tetrahydrofuran, DMSO means dimethyl sulphoxide, andDCM means dichloromethane, DMF means N,N-dimethylformamide, NMP meansN-methyl-2-pyrrolidinone;

[0164] AcOH means acetic acid, TFA means trifluoroacetic acid;

[0165] Me means methyl, Et means ethyl;

[0166] Cl means chloro; and

[0167] OH means hydroxy.

[0168] The following schemes illustrate the preparation of compounds ofthe formula (I), throughout which Rings A and B, and groups V, W, X, Y,and n are as defined above unless otherwise stated. (I′) represents (I)when W is NR¹.

[0169] Step (a): Oxadiazole (II) is reacted with an acid catalyst togive the compound of formula (I). Typically the reaction is carried outby heating the starting materials to elevated temperatures, such as50-150° C., for 1 to 48 hours with a suitable acidic catalyst such asp-TSA, trifluoroacetic acid or Lewis acid catalyst such as magnesiumchloride, optionally using a solvent such as xylene, toluene ortetrahydrofuran. Preferred conditions are:

[0170] amine (II) and cat. P-TSA, in xylene at 140° C. for 48 hours; oramine (II), trifluoroacetic acid in tetrahydrofuran at 60° C. for 24hours.

[0171] When W=NR¹, then:

[0172] Z′ is OH or halo, typically Cl

[0173] Compounds suitable for use as compound (VI) are commerciallyavailable or are known in the literature.

[0174] Step (b): The reaction of amine (V) with compound (VI) can becarried out by standard methods.

[0175] When R¹=(CH₂)_(b)COR², CO(CH₂)_(b)NR²R³, SO₂R² then, typically,the coupling may be undertaken by using:

[0176] (i) an acyl/sulphonyl/chloride (VI)+amine (V) with an excess ofacid acceptor, in a suitable solvent; or

[0177] (ii) an acid (VI) with a conventional coupling agent+amine (V),optionally in the presence of a catalyst, with an excess of acidacceptor in a suitable solvent; and

[0178] (iii) when R¹ represents an aryl group, an aryl halide (VI)+amine(V), optionally in the presence of a catalyst, with an excess of acidacceptor in a suitable solvent.

[0179] Typically the conditions are as follows:

[0180] Acylation/Sulphonylation, Z′═Cl

[0181] (i) An excess of acyl/sulphonyl chloride (VI) (generatedin-situ), 1 eq. of amine (V), optionally with an excess of 30 amine suchas Et₃N, Hünig's base or NMM, in DCM or THF, without heating for 1 to 24hours.

[0182] The preferred conditions are:

[0183] Amine (V), 1.1-3.0 eq. acid/sulphonyl chloride (VI), 1.5-3 eq.NMM, Et₃N or pyridine in DCM at room temperature for 1-16 hours.

[0184] Amide Bond Formation, Z′═OH

[0185] (ii) Excess acid (VI), WSCDI/DCC and HOBT/HOAT, 1 eq. of amine(V), with an excess of NMM, Et₃N, Hünig's base in THF, DCM or EtOAc, atroom temperature for 4 to 48 hours; or

[0186] excess acid (VI), PYBOP®/PyBrOP®/Mukaiyama's reagent/HBTU, 1 eq.of amine (V), with an excess of NMM, Et₃N, Hünig's base in THF, DCM orEtOAc, at room temperature for 4 to 24 hours.

[0187] The preferred conditions are:

[0188] amine (V), 2 eq. HBTU, 2eq acid (R¹OH) in DCM at room temperaturefor 18 hours; or

[0189] amine (V) HOBT, WSCDI, Et₃N, in DCM at room temperature for 18hours.

[0190] Arylation (R¹=Aryl, heteroaryl), Z′=halo

[0191] (iii) Arylation of compound (V) can be carried out by a palladiumcatalysed cross-coupling reaction using a suitable base (t-BuONa), acatalytic amount of suitable additive such as2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and a suitable palladiumcatalyst in toluene at elevated temp for 1 to 24 hours under an inertatmosphere, to give compound (I′). Alternatively compound (I′) can beprepared by reaction of the amine (V) with compound (VI) by heating atelevated temperature, such as 50° C.-140° C., in a suitable solvent suchas DMF, NMP or 1,4-dioxan for about 1-48 hours with a base such aspotassium carbonate, sodium hydrogen carbonate or Hünig's base.

[0192] Preferred conditions are:

[0193] 1-2.5 eq. halide (VI), 1-2 eq. potassium carbonate inN,N-dimethylformamide at 50-95° C. for 4-18 hours; or

[0194] 1-2.5 eq. halide (VI), 2-3 eq. Hünig's base, in 1,4-dioxan or NMPat reflux for 18-48 hours; or

[0195] 1 eq. halide (VI), 3.5 eq. NaOt-Bu, 0.08 eq BINAP, 0.4 eq.Pd(dba)₂, in toluene for 8 hours at 70° C.

[0196] Alkylation (R¹=substituted alkyl), Z′=halo, preferably Br or Cl

[0197] Alkylation of compound (V) can be performed by reaction with asuitable alkylating agent, R¹Z′ in the presence of a suitable tertiaryamine (NMM, Et₃N or Hünig's base) or alkali metal base (K₂CO₃, Cs₂CO₃)in a suitable solvent (MeCN, DMF), at about room temperature.

[0198] The preferred conditions are:

[0199] amine (V) R¹Z′, excess K₂CO₃ or Hünig's base in DMF for 18 hoursat room temperature.

[0200] Alternatively, compounds (I′) may be prepared by the route shownbelow in Scheme 1.3.

[0201] Compounds suitable for use as compound (VII) are commerciallyavailable or are known in the literature.

[0202] Step (c): Amine (V) is reacted with an excess of aldehyde/ketone(VII) in the presence of a reducing agent, such as sodiumtriacetoxyborohydride or sodium cyanoborohydride, to give the compoundof formula (I′). This reaction may be carried out by:

[0203] stirring the starting materials at temperatures such as 20°C.-80° C. for 1 to 48 hours in a suitable solvent such asdichloromethane, or

[0204] heating amine (V) with excess compound (VII) with a suitableLewis acid catalyst such as titanium tetrachloride or titaniumtetraisopropoxide at temperatures such as 50° C.-100° C. in a suitablesolvent such as dichloroethane or ethanol for 1-18 hours, followed byreduction of the intermediate imine/iminium species with a suitablereducing agent, such as sodium borohydride, or hydrogenolysis over asuitable catalyst, such as platinum oxide or palladium on carbon.

[0205] Preferred conditions are:

[0206] amine (V), 1-1.5 eq. aldehyde/ketone (VII), 1-2.0 eq. sodiumtriacetoxy borohydride in dichloromethane, optionally in the presence ofAcOH at room temperature for 2 hours.

[0207] When ring B is linked to ring A via an N atom, and W represents Oor S then:

[0208] Prot represents a suitable protecting group for nitrogen, forexample Boc, CBz or Allyl carbamate. Standard methodology for nitrogenprotecting groups is used, such as that found in textbooks (e.g.“Protecting Groups in Organic Synthesis” by T. W. Greene and P. Wutz).Z″ represents a leaving group such as halogen.

[0209] Compounds suitable for use as compound (IV) are commerciallyavailable or are known in the literature.

[0210] Arylation of compound (III) can be carried out as described inStep (b) above.

[0211] Preferred conditions are:

[0212] 1-2.5 eq. halide (IV), 1-2 eq. potassium carbonate inN,N-dimethylformamide at 50° C. for 4-18 hours; or

[0213] 1-2.5 eq. halide (IV), 2-3 eq. Hünig's base, in 1,4-dioxan or NMPat reflux for 18-48 hours; or p1 1 eq. halide (IV), 3.5 eq. NaOt-Bu,0.08 eq BINAP, 0.4 eq. Pd(dba)₂, in toluene for 8 hours at 70° C.

[0214] Step (d): Deprotection of compound (IX) is undertaken usingstandard methodology, as described in “Protecting Groups in OrganicSynthesis” by T. W. Greene and P. Wutz”.

[0215] When Prot is Boc, the preferred methods are:

[0216] hydrogen chloride in a suitable solvent such as 1,4-dioxane atroom temperature for 1-16 hours; or

[0217] a solution of trifluoroacetic acid in dichloromethane for 1-2hours.

[0218] When Prot is CBz, the preferred method is hydrogenolysis using asuitable palladium catalyst in a solvent such as ethanol.

[0219] When Prot is an allyl carbamate, preferred conditions arethiobenzoic acid and a suitable palladium catalyst such as Pd₂(Dba)₃with a suitable phosphine additive such as1,4-bis(diphenylphosphino)butane in tetrahydrofuran for 20 minutes.

[0220] When ring B is linked to ring A via an N atom, and W representsNR¹ then:

[0221] Prot represents a suitable protecting group for nitrogen, forexample Boc, CBz or Allyl carbamate. Standard methodology for nitrogenprotecting groups is used, such as that found in textbooks, (e.g.“Protecting Groups in Organic Synthesis” by T. W. Greene and P. Wutz).

[0222] Z′ represents a leaving group (typically Cl or OH). Z″ representshalo (typically Cl).

[0223] Compounds suitable for use as compound (IV) are commerciallyavailable or are known in the literature.

[0224] Compound (IX″) typically can be prepared from compound (IX′)using the methodology described in Step (b) and Step (c) above.

[0225] Compound (III′) typically can be prepared from compound (IX″)using the methodology described in Step (d) above.

[0226] Compounds (I′) typically can be prepared by arylation ofcompounds (III′) using the methodology described in Step (b) above.

[0227] Compounds suitable for use as compounds (II) and (VIII) are knownin the literature or can be prepared as shown in Schemes 3.1, 3.2 and3.3 below.

[0228] LG represents a leaving group, typically halo, and preferablychloro or bromo.

[0229] When rings A and B are linked through an N atom then:

[0230] LG is a leaving group, typically halo, and preferably chloro orbromo

[0231] Compounds suitable for use as compounds (XI) are known in theliterature or can be prepared using standard methodology: for example,reduction of benzoic acids (see preparation 7 below) or benzonitriles(see preparation 10 below) or nitrobenzenes (preparations 57 and 58).

[0232] When W represents NR¹:

[0233] Step (e): Compound (X)/(XII) is reacted with an excess ofcompound (XI) to give compound (II)/(VIII) respectively, optionally inthe presence of an excess of base, such as triethylamine, Hünig's baseor NMM or potassium carbonate as proton acceptor, optionally in thepresence of a catalyst (e.g. Nal) in a suitable high boiling solventsuch as THF, Toluene or DMF at temperatures from 50° C. to 100° C. for 1to 48 hours.

[0234] Preferred conditions are:

[0235] 2.5 eq. of compound (XI) in THF at 50° C. for 48 hours; or

[0236] 1.1 eq compound (XI) 1.1 eq NMM or K₂CO₃, 0.5 eq. Nal in THF at50° C.

[0237] When W represents O or S:

[0238] Step (e): Compound (X)/(XII) is reacted with an excess ofcompound (XI) in the presence of a base such as sodium hydride,potassium hexamethyidisilazide, butyl lithium or isopropyl magnesiumchloride, in a suitable solvent such as THF, Toluene or NMP attemperatures from 0° C. to 50° C. for 1 to 24 hours, to give compound(II)/(VIII) respectively.

[0239] Preferred conditions are:

[0240] 1.1-3 eq. of compound (XI) and 1.1-2.5 eq. of NaH in THF at 20°C. for 2 hours.

[0241] When W=NR¹, and Z=CO then

[0242] Step (i): Amine (XX) may be prepared by amination of compound (X)with the amine R¹NH₂ in a solvent such as ethanol or tetrahydrofuran at25-75° C. for 5-72 hours.

[0243] Preferred conditions are:

[0244] Compound (X), excess of R¹NH₂ in ethanol and THF at roomtemperature for about 72 hours.

[0245] Compound (II) may be prepared by coupling of the amine (XX) withthe acid (XXI) according to the procedure described previously in step(b).

[0246] Compounds suitable for use as compounds (X) and (XII) are knownin the literature or can be prepared as shown in Schemes 4.1 and 4.2.

[0247] X¹ represents OH or halo, and preferably represents Cl. LGrepresents a leaving group, typically halo, and preferably chloro orbromo

[0248] When rings A and B are linked through an N atom then:

[0249] X¹ represents OH or halo, and preferably represents Cl. LG is aleaving group, typically halo, and preferably chloro or bromo

[0250] Compound (XIV) is either commercially available or is known inthe literature.

[0251] Step (f): The reaction of hydrazide (XIII/XIII′) with compound(XIV) can be carried out by standard methods.

[0252] Coupling may be undertaken by using either:

[0253] (i) an acyl chloride (XIV)+hydrazide (XIII/XIII′) with an excessof acid acceptor in a suitable solvent; or

[0254] (ii) acid (XIV) with a conventional coupling agent+hydrazide(XIII/XIII′), optionally in the presence of a catalyst, with an excessof acid acceptor in a suitable solvent.

[0255] Typically the conditions are as follows:

[0256] (i) acid chloride (XIV) (generated in-situ), an excess ofhydrazide (XIII/XIII′) optionally with an excess of 3° amine such asEt₃N, Hünig's base or NMM, in DCM or THF, without heating for 1 to 24hours; or

[0257] (ii) acid (XIV), WSCDI/DCC and HOBT/HOAT, an excess of hydrazide(XIII/XIII′), with an excess of NMM, Et₃N, Hünig's base in THF, DCM orEtOAc, at room temperature for 4 to 48 hours; or

[0258] (ii) acid (XIV), PYBOP®/PyBrOP®/Mukaiyama's reagent, an excess ofhydrazide (XIII/XII′), with an excess of NMM, Et₃N, Hünig's base in THF,DCM or EtOAc, at room temperature for 4 to 24 hours.

[0259] The preferred conditions are:

[0260] Hydrazide (XIII/XIII′), 1.5 eq. chloro acetyl chloride (XIV), 1.5eq. NMM in DCM at room temperature for 16 hours.

[0261] Step (g): Cyclisation of compound (XV/XV′) is carried out undersuitable dehydrating conditions, at elevated temperatures for up to 18hours. Typically, dehydrating agents such as polyphosphoric acid,phosphorous oxychloride, triflic anhydride are used at temperatures from20 to 120° C. for 5 minutes to 12 hours. Optionally, the reaction can becarried out in the presence of a base such as pyridine and suitablesolvents such as dichloromethane and acetonitrile. Alternatively, theoxadiazole (XII/X) may be prepared according to the method of Rigo et.al. Synth. Commun. 16(13), 1665, 1986.

[0262] Preferred conditions are:

[0263] phosphorous oxychloride at 100° C. for 8 hours, or 2.5 eq.triflic anhydride in acetonitrile at 20° C. for 5 hours.

[0264] Compounds suitable for use as compounds (XIII/XIII′) are known inthe literature or can be prepared as shown in Schemes 5.1 and 5.2.

[0265] When rings A and B are linked through an N atom then:

[0266] Compounds (XVI)/(XVI′) and protected hydrazine are eithercommercially available or are known in standard methodology such as thehydrolysis of the corresponding ester.

[0267] Carboxylic acid (XVI)/(XVI′) and protected hydrazine, where prot*is typically Boc, may be coupled to give compound (XVII/XVII′)respectively, using the conditions described above for the preparationof (XV/XV′), and then prot* is removed using standard methodology asdescribed in Step (d) as described above, to give (XIII/XIII′).

[0268] Alternative routes to compound (XIII/XIII′) are shown below inSchemes 6.1 and 6.2:

[0269] R is typically C₁₋₂ alkyl

[0270] When rings A and B are linked through an N atom then:

[0271] Step (h): The ester (XVIII/XVIII′) may be reacted with hydrazinein a suitable solvent, such as methanol, at an elevated temperature toprovide the hydrazide (XVII/XVII′). Preferred conditions:

[0272] 3 eq. hydrazine, in methanol, at reflux for 18 hours.

[0273] Alternatively, compounds of formula (I) may be prepared accordingto the Scheme 7.0 below.

[0274] R=H or C₁-C₄ alkyl, typically tert-butyl, methyl or ethyl

[0275] When R=H,

[0276] Compounds of formula (XXIII) may be prepared by anintra-molecular coupling of the amino acid (XXII), according to theprocedure previously described in step (b). Preferably, compound (XXII)is treated with 1.4 eq. HBTU, 4.5 eq. NMM in DCM at room temperature forabout 18 hours.

[0277] When R=C₁-C₄ alkyl:

[0278] Compounds of formula (XXIII) may be prepared by base catalysedcyclisation of the amino ester (XXII) typically carried out at roomtemperature or below for 1-5 hours. Typically, bases such as potassiumtert-butoxide, sodium ethoxide or isopropyl magnesium chloride are usedat or below 20° C. in a suitable solvent such as tetrahydrofuran orethanol for 1-5 hours.

[0279] Preferably, compound (XXII) is treated with 1.1 eq. potassiumter-butoxide in THF at 20° C. for about 2 hours.

[0280] Step (j): Formation of Thioamide

[0281] Thionation of the amide (XXIII) using a suitable thionating agent(e.g. Lawesson's reagent, P₄S₁₀), and optionally in the presence of abase (e.g. Na₂CO₃) in a suitable solvent (e.g. THF) at between 0° C. androom temperature. Preferred conditions are:

[0282] 1 eq. P₄S₁₀, 1 eq. Na₂CO₃, 1 eq. amide (XXIII) in THF at between3-25° C. for 18-72 hours

[0283] Step (k): Thioimidate Formation

[0284] Treatment of the thioamide (XXIV) with a strong base such asKO^(t)Bu or LDA, in a suitable solvent such as THF or ether, followed byquench of the anion formed by a suitable methyl source (e.g. Mel, Mep-tosylate) provides the thioimidate (XXV).

[0285] Preferred conditions are:

[0286] 1 eq. thioamide (XXIV), treated with 1 eq. KO^(t)Bu, 1 eq. Mep-tosyalte in THF.

[0287] Triazole Formation:

[0288] Step (I): The thioimidate (XXV) is treated with the hydrazide(XIII) in a suitable solvent, typically ethanol at elevated temperatureto provide the compound of formula (I), optionally in the presence of anacid catalysed such as TFA, p-TSA.

[0289] Preferred conditions are:

[0290] 1 eq. thioimidate (XXV), 1 eq. hydrazide (XIII), in ethanol atreflux for 2 hours.

[0291] Step (m): The thioamide (XXIV) is treated with the hydrazide(XIII) in a suitable solvent, typically n-Butan-1-ol at elevatedtemperature to provide the compound of formula (I), optionally in thepresence of an acid catalysed such as TFA, p-TSA.

[0292] Preferred conditions are:

[0293] 1 eq. Thioamide (XXIV), 1 eq. hydrazide (XIII), in n-butan-1-olat reflux for 18 hours.

[0294] Compounds suitable for use as compounds (XXII) are known in theliterature or can be prepared using standard methodology, for examplesee C. Apfel et.al., J.Med. Chem. 44(12), 1847-1852, 2001, C. P. Langet. al., WO2002008228, F. Ishikawa, J.Med. Chem. 28(10), 1387-93, 1985or Uskokovic, M. et. al., Journal of Organic Chemistry (1965), 30(9),3111-14.

[0295] It will be apparent to those skilled in the art that sensitivefunctional groups may need to be protected and deprotected duringsynthesis of a compound of formula (I). This may be achieved byconventional techniques, for example as described in “Protective Groupsin Organic Synthesis” by T W Greene and P G M Wuts, John Wiley and SonsInc, 1991, exemplified by examples 42-49 and 55-58.

[0296] Certain compounds of formula (I) may be converted to alternativecompounds of formula (I) using standard chemical transformations.Examples of these are illustrated below:

[0297] Amination (e.g. examples 40 & 41)

[0298] When R¹ contains a leaving group, such as a chloro substituent,this may react with a suitable amine HNR²R³ in the presence of asuitable tertiary amine base (Et₃N, NMM or Hünig's base) or alkali metalbase (K₂CO₃, Cs₂CO₃) in a suitable solvent (e.g. DMF, MeCN), optionallyat elevated temperature. Preferably, the chloro compound is treated withan excess of HNR²R³, in the presence of an excess of K₂CO₃ in DMF at 70°C.

[0299] Reduction (e.g. examples 50-54, 64 & 65)

[0300] Compounds containing a carbonyl function may be reduced using asuitable reducing agent such as DIBAL or borane in a suitable solventsuch as ether or THF at or between room temperature and the refluxtemperature of the reaction. Preferably, the amide compound is treatedwith 10 eq. borane in THF at reflux, followed by an excess of HCl atreflux.

[0301] Reductive amination (e.g. examples 69-81 & 84-90)

[0302] Compounds of formula (I) containing a reactive N atom may reactwith an aldehyde or ketone, according to the methods described in step(c). Preferably, the amine of formula (I) is treated with an excess ofaldehyde/ketone and 2 eq. Na(OAc)₃BH in DCM, optionally in the presenceof an excess of Et₃N and acetic acid, at room temperature for up to 18hours.

[0303] Oxidation (e.g. When W═S)

[0304] Compounds of formula (I) containing a Sulphur atom may beoxidised using a suitable oxidising agent such as hydrogen peroxide ormeta-chloro perbenzoic acid in a suitable solvent such astrifluoroacetic acid or 1,1,1,3,3,3-Hexafluoro-propan-2-ol between 0-25°C.

[0305] When oxidising to sulphoxide (W═S(O)₁), preferably the sulphideof formula (I) is treated with 1-1.2 eq. of 30% aqueous hydrogenperoxide in 1,1,1,3,3,3-Hexafluoro-propan-2-ol at room temperature forup to 1 hour.

[0306] When oxidising to sulphone (W═S(O)₂), preferably the sulphide offormula (I) is treated with 2-3 eq. of 30% aqueous hydrogen peroxide intrifluoroacetic acid for up to 1 hour.

[0307] (Alternatively, the sulphoxide (W═S(O)₁) above may be oxidised tothe sulphone (W═S(O)₂) using 1-2 eq. of 30% aqueous hydrogen peroxide intrifluoroacetic acid for up to 1 hour.)

[0308] In accordance with the present invention there is furtherprovided an intermediate of formula (II):

[0309] an intermediate of formula (III):

[0310] an intermediate of formula (X):

[0311] an intermediate of formula (XV):

[0312] an intermediate of formula (XXIV):

[0313] an intermediate of formula (XXV):

[0314] wherein V, W, X, Y, Z, rings A and B, LG and n are as definedabove.

[0315] The compounds of the present invention are useful because theypossess pharmacological activity in animals. In particular they areuseful in the treatment of a number of conditions including aggression,Alzheimer's disease, anorexia nervosa, anxiety, anxiety disorder,asthma, atherosclerosis, autism, cardiovascular disease (includingangina, atherosclerosis, hypertension, heart failure, edema,hypernatremia), cataract, central nervous system disease,cerebrovascular ischemia, cirrhosis, cognitive disorder, Cushing'sdisease, depression, diabetes mellitus, dysmenorrhoea (primary andsecondary), emesis (including motion sickness), endometriosis,gastrointestinal disease, glaucoma, gynaecological disease, heartdisease, intrauterine growth retardation, inflammation (includingrheumatoid arthritis), ischemia, ischemic heart disease, lung tumor,micturition disorder, mittlesmerchz, neoplasm, nephrotoxicity,non-insulin dependent diabetes, obesity, obsessive/compulsive disorder,ocular hypertension, preclampsia, premature ejaculation, premature(preterm) labor, pulmonary disease, Raynaud's disease, renal disease,renal failure, male or female sexual dysfunction, septic shock, sleepdisorder, spinal cord injury, thrombosis, urogenital tract infection orurolithiasis.sleep disorder, spinal cord injury, thrombosis, urogenitaltract infection, urolithiasis. Particularly of interest is dysmenorrhoea(primary or secondary), more particularly, primary dysmenorrhoea.

[0316] Thus, according to another aspect of the invention, there isprovided a method of treatment of dysmenorrhoea which comprisesadministering a therapeutically effective amount of a compound of theinvention to a patient suffering from anxiety, cardiovascular disease(including angina, atherosclerosis, hypertension, heart failure, edema,hypernatremia), dysmenorrhoea (primary and secondary), endometriosis,emesis (including motion sickness), intrauterine growth retardation,inflammation (including rheumatoid arthritis), mittlesmerchz,preclampsia, premature ejaculation, premature (preterm) labor orRaynaud's disease. The use of the compounds as a medicament and the useof the compounds of the present invention in the manufacture of amedicament for the treatment of anxiety, cardiovascular disease(including angina, atherosclerosis, hypertension, heart failure, edema,hypernatremia), dysmenorrhoea (primary and secondary), endometriosis,emesis (including motion sickness), intrauterine growth retardation,inflammation (including rheumatoid arthritis), mittlesmerchz,preclampsia, premature ejaculation, premature (preterm) labor orRaynaud's disease, particularly dysmenorrhoea, are also provided.

[0317] Compounds of the invention intended for pharmaceutical use may beadministered as crystalline or amorphous products. They may be obtained,for example, as solid plugs, powders, or films by methods such asprecipitation, crystallisation, freeze drying, spray drying, orevaporative drying. Microwave or radio frequency drying may be used forthis purpose.

[0318] They may be administered alone or in combination with one or moreother compounds of the invention or in combination with one or moreother drugs (or as any combination thereof). For example, the compoundsof the present invention may be administered in combination with an oralcontraceptive. Alternatively, they may be administered in combinationwith a PDE5 inhibitor. They may also be administered in combination withan NO donor. Alternatively, they may be administered in combination withL-arginine, or as an arginate salt. The compounds of the presentinvention may also be used in combination with a COX inhibitor.

[0319] Generally, they will be administered as a formulation inassociation with one or more pharmaceutically acceptable excipients. Theterm “excipient” is used herein to describe any ingredient other thanthe compound(s) of the invention. The choice of excipient will to alarge extent depend on factors such as the particular mode ofadministration, the effect of the excipient on solubility and stability,and the nature of the dosage form.

[0320] Pharmaceutical compositions suitable for the delivery ofcompounds of the present invention and methods for their preparationwill be readily apparent to those skilled in the art. Such compositionsand methods for their preparation may be found, for example, in“Remington's Pharmaceutical Sciences”, 19^(th) Edition (Mack PublishingCompany, 1995).

[0321] Thus, according to another aspect of the present invention, thereis provided a pharmaceutical formulation comprising a compound offormula (I) in admixture with a pharmaceutically acceptable adjuvant,diluent or carrier.

[0322] The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, or buccal or sublingual administration may beemployed by which the compound enters the blood stream directly from themouth.

[0323] Formulations suitable for oral administration include solidformulations such as tablets, capsules containing particulates, liquidsor powders, lozenges (including liquid-filled), chews, multi- andnano-particulates, gels, solid solution, liposome, films (includingmuco-adhesive), ovules, sprays and liquid formulations.

[0324] Liquid formulations include suspensions, solutions, syrups andelixirs. Such formulations may be employed as fillers in soft or hardcapsules and typically comprise a carrier, for example water, ethanol,polyethylene glycol, propylene glycol, methylcellulose, or a suitableoil, and one or more emulsifying agents and/or suspending agents. Liquidformulations may also be prepared by the reconstitution of a solid, forexample from a sachet.

[0325] The compounds of the invention may also be used infast-dissolving, fast disintegrating dosage forms such as thosedescribed in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 byLiang and Chen (2001).

[0326] For tablet dosage forms, depending on dose, the drug may make upfrom 1 wt % to 80 wt % of the dosage form, more typically from 5 wt % to60 wt % of the dosage form. In addition to the drug, tablets generallycontain a disintegrant. Examples of disintegrants include sodium starchglycolate, sodium carboxymethyl cellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone,methyl cellulose, microcrystalline cellulose, lower alkyl-substitutedhydroxypropyl cellulose, starch, pregelatinised starch and sodiumalginate. Generally, the disintegrant will comprise from 1 wt % to 25 wt%, preferably from 5 wt % to 20 wt %, of the dosage form.

[0327] Binders are generally used to impart cohesive qualities to atablet formulation. Suitable binders include microcrystalline cellulose,gelatin, sugars, polyethylene glycol, natural and synthetic gums,polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose andhydroxypropyl methylcellulose. Tablets may also contain diluents, suchas lactose (monohydrate, spray-dried monohydrate, anhydrous and thelike), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystallinecellulose, starch and dibasic calcium phosphate dihydrate.

[0328] Tablets may also optionally comprise surface active agents, suchas sodium lauryl sulfate and polysorbate 80, and glidants such assilicon dioxide and talc. When present, surface active agents maycomprise from 0.2 wt % to 5 wt % of the tablet, and glidants maycomprise from 0.2 wt % and 1 wt % of the tablet.

[0329] Tablets also generally contain lubricants such as magnesiumstearate, calcium stearate, zinc stearate, sodium stearyl fumarate, andmixtures of magnesium stearate with sodium lauryl sulphate. Lubricantsgenerally comprise from 0.25 wt % to 10 wt %, preferably from 0.5 wt %to 3 wt %, of the tablet.

[0330] Other possible ingredients include anti-oxidants, colourants,flavouring agents, preservatives and taste-masking agents.

[0331] Exemplary tablets contain up to about 80% drug, from about 10 wt% to about 90 wt % binder, from about 0 wt % to about 85 wt % diluent,from about 2 wt % to about 10 wt % disintegrant, and from about 0.25 wt% to about 10 wt % lubricant.

[0332] Tablet blends may be compressed directly or by roller to formtablets. Tablet blends or portions of blends may alternatively be wet-,dry-, or melt-granulated, melt congealed, or extruded before tabletting.The final formulation may comprise one or more layers and may be coatedor uncoated; it may even be encapsulated.

[0333] The formulation of tablets is discussed in “Pharmaceutical DosageForms: Tablets, Vol. 1”, by H. Lieberman and L. Lachman, Marcel Dekker,N.Y., N.Y., 1980 (ISBN 0-8247-6918-X).

[0334] Solid formulations for oral administration may be formulated tobe immediate and/or modified release. Modified release formulationsinclude delayed-, sustained-, pulsed-, controlled-, targeted- andprogrammed release.

[0335] Suitable modified release formulations for the purposes of theinvention are described in U.S. Pat. No. 6,106,864. Details of othersuitable release technologies such as high energy dispersions andosmotic and coated particles are to be found in Verma et al,Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use ofchewing gum to achieve controlled release is described in WO 00/35298.

[0336] The compounds of the invention may also be administered directlyinto the blood stream, into muscle, or into an internal organ. Suitablemeans for parenteral administration include intravenous, intraarterial,intreperitoneal, intrathecal, intraventricular, intraurethral,intrasternal, intracranial, intramuscular and subcutaneous. Suitabledevices for parenteral administration include needle (includingmicroneedle) injectors, needle-free injectors and infusion techniques.

[0337] Parenteral formulations are typically aqueous solutions which maycontain excipients such as salts, carbohydrates and buffering agents(preferably to a pH of from 3 to 9), but, for some applications, theymay be more suitably formulated as a sterile non-aqueous solution or asa dried form to be used in conjunction with a suitable vehicle such assterile, pyrogen-free water. The preparation of parenteral formulationsunder sterile conditions, for example, by lyophilisation, may readily beaccomplished using standard pharmaceutical techniques well known tothose skilled in the art.

[0338] The solubility of compounds of formula (I) used in thepreparation of parenteral solutions may be increased by suitableprocessing, for example, the use of high energy spray-dried dispersions(see WO 01/47495) and/or by the use of appropriate formulationtechniques, such as the use of solubility-enhancing agents.

[0339] Formulations for parenteral administration may be formulated tobe immediate and/or modified release. Modified release formulationsinclude delayed-, sustained-, pulsed-, controlled-, targeted- andprogrammed release. Thus, compounds of the invention may be formulatedas a solid, semi-solid, or thixotropic liquid for administration as animplanted depot providing modified release of the active compound.Examples of such formulations include drug-coated stents and PGLAmicrospheres.

[0340] The compounds of the invention may also be administered topicallyto the skin or mucosa, either dermally or transdermally. Typicalformulations for this purpose include gels, hydrogels, lotions,solutions, creams, ointments, dusting powders, dressings, foams, films,skin patches, wafers, implants, sponges, fibres, bandages andmicroemulsions. Liposomes may also be used. Typical carriers includealcohol, water, mineral oil, liquid petrolatum, white petrolatum,glycerin, polyethylene glycol and propylene glycol. Penetrationenhancers may be incorporated—see, for example, J. Pharm. Sci., 88 (10),955-958 by Finnin and Morgan (October 1999).

[0341] Other means of topical administration include delivery byiontophoresis, electroporation, phonophoresis, sonophoresis andmicroneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.

[0342] Formulations for topical administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

[0343] The compounds of the invention can also be administeredintranasally or by inhalation, typically in the form of a dry powder(either alone, as a mixture, for example, in a dry blend with lactose,or as a mixed component particle, for example, mixed with phospholipids,such as phosphatidylcholine) from a dry powder inhaler or as an aerosolspray from a pressurised container, pump, spray, atomiser (preferably anatomiser using electrohydrodynamics to produce a fine mist), ornebuliser, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane.

[0344] For intranasal use, the powder may comprise a bioadhesive agent,for example, chitosan or cyclodextrin.

[0345] The pressurised container, pump, spray, atomizer or nebulisercontains a solution or suspension of the compound(s) of the inventioncomprising, for example, ethanol, aqueous ethanol, or a suitablealternative agent for dispersing, solubilising or extending release ofthe active, the propellant(s) as solvent and an optional surfactant,such as sorbitan trioleate, oleic acid, or an oligolactic acid.

[0346] Prior to use in a dry powder of suspension formulation, the drugproduct is micronised to a size suitable for delivery by inhalation(typically less than 5 microns). This may be achieved by any appropriatecomminuting method, such a spiral jet milling, fluid bed jet milling,supercritical fluid processing to form nanoparticles, high pressurehomogenisation or spray drying.

[0347] Capsules (made, for example, from gelatin or HPMC), blisters andcartridges for use in an inhaler or insufflator may be formulated tocontain a powder mix of the compound of the invention, a suitable powderbase such as lactose or starch and a performance modifier such asI-leucine, mannitol, or magnesium stearate. The lactose may be anhydrousor in the form of the monohydrate, preferably the latter. other suitableexcipients include dextran, glucose, maltose, sorbitol, xylitol,fructose, sucrose and trehalose. A suitable solution formulation for usein an atomiser using electrohydrodynamics to produce a fine mist maycontain from 1 μg to 20 mg of the compound of the invention peractuation and the actuation volume may vary from 1 μl to 100 μl. Atypical formulation may comprise a compound of formula (I), propyleneglycol, sterile water, ethanol and sodium chloride. Alternative solventswhich may be used instead of propylene glycol include glycerol andpolyethylene glycol.

[0348] Suitable flavours, such as menthol and levomenthol, orsweeteners, such as saccharin or saccharin sodium, may be added to thoseformulations of the invention intended for inhaled/intranasaladministration.

[0349] Formulations for inhaled/intranasal administration may beformulated to be immediate and/or modified release using, for example,poly-DL-lactic-coglycolic acid (PGLA). Modified release formulationsinclude delayed-, sustained-, pulsed-, controlled-, targeted andprogrammed release.

[0350] The compounds of the invention may be administered rectally orvaginally, for example, in the form of a suppository, pessary or enema.Cocoa butter is a traditional suppository base, but various alternativesmay be used as appropriate.

[0351] Formulations for rectal/vaginal administration may be formulatedto be immediate and/or modified release. Modified release formulationsinclude delayed-, sustained-, pulsed-, controlled-, targeted andprogrammed release.

[0352] The compounds of the invention may also be administered directlyto the eye or ear, typically in the form of drops of a micronisedsuspension or solution in isotonic, pH-adjusted, sterile saline. Otherformulations suitable for ocular and aural administration includeointments, biodegradable (e.g. absorbable gel sponges, collagen) andnon-biodegradable (e.g. silicone) implants, wafers, lenses andparticulate or vesicular systems, such as niosomes or liposomes. Apolymer such as crossed-linked polyacrylic acid, polyvinylalcohol,hyaluronic acid, a cellulosic polymer, for example,hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum,may be incorporated together with a preservative, such as benzalkoniumchloride. Such formulations may also be delivered by iontophoresis.

[0353] Formulations for ocular/aural administration may be formulated tobe immediate and/or modified release. Modified release formulationsinclude delayed-, sustained-, pulsed-, controlled-, targeted, orprogrammed release.

[0354] The compounds of the invention may be combined with solublemacromolecular entities such as cyclodextrin or polyethyleneglycol-containing polymers to improve their solubility, dissolutionrate, taste-masking, bioavailability and/or stability for use in any ofthe aforementioned modes of administration.

[0355] Drug-cyclodextrin complexes, for example, are found to begenerally useful for most dosage forms and administration routes. Bothinclusion and non-inclusion complexes may be used. As an alternative todirect complexation with the drug, the cyclodextrin may be used as anauxiliary additive, i.e. as a carrier, diluent or solubiliser. Mostcommonly used for these purposes are alpha-, beta- andgamma-cyclodextrins, examples of which may be found in InternationalPatent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.

[0356] Inasmuch as it may be desirable to administer a combination ofactive compounds, for example, for the purpose of treating a particulardisease or condition, it is within the scope of the present inventionthat two or more pharmaceutical compositions, at least one of whichcontains a compound in accordance with the invention, may convenientlybe combined in the form of a kit suitable for coadministration of thecompositions.

[0357] Thus the kit of the invention comprises two or more separatepharmaceutical compositions, at least one of which contains a compoundsof formula (I) in accordance with the invention, and means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is the familiarblister pack used for the packaging of tablets, capsules and the like.

[0358] The kit of the invention is particularly suitable foradministering different dosage forms, for example, oral and parenteral,for administering the separate compositions at different dosageintervals, or for titrating the separate compositions-against oneanother. To assist compliance, the kit typically comprises directionsfor administration and may be provided with a so-called memory aid.

[0359] For administration to human patients, the total daily dose of thecompounds of the invention will typically be in the range of from about0.01 to about 15 mg/kg of body weight, depending on the mode ofadministration. The total daily dose may be administered in a singledose or divided doses throughout the day. These dosages are based on anaverage human subject having a weight of about 65 kg to 70 kg. Thephysician will readily be able to determine doses for subjects whoseweight falls outside this range, such as infants and the elderly.

[0360] As used herein, the terms “treating” and “to treat”, mean toalleviate symptoms, eliminate the causation either on a temporary orpermanent basis, or to prevent or slow the appearance of symptoms. Theterm “treatment” includes alleviation, elimination of causation (eitheron a temporary or permanent basis) of, or prevention of symptoms anddisorders associated with primary and/or secondary dysmenorrhoea. Thetreatment may be a pre-treatment as well as a treatment at the on-set ofsymptoms.

[0361] The compounds of the present invention may be tested in thescreens set out below:

[0362] 1.0 V_(1A) Filter Binding Assay

[0363] 1.1 Membrane Preparation

[0364] Receptor binding assays were performed on cellular membranesprepared from CHO cells stably expressing the human V_(1A) receptor,(CHO-hV_(1A)). The CHO-hV_(1A) cell line was kindly provided under alicensing agreement by Marc Thibonnier, Dept. of Medicine, Case WesternReserve University School of Medicine, Cleveland, Ohio. CHO-hV_(1A)cells were routinely maintained at 37° C. in humidified atmosphere with5% CO₂ in DMEM/Hams F12 nutrient mix supplemented with 10% fetal bovineserum, 2 mM L-glutamine, 15 mM HEPES and 400 μg/ml G418. For bulkproduction of cell pellets, adherent CHO-hV_(1A) cells were grown toconfluency of 90-100% in 850 cm² roller bottles containing a medium ofDMEM/Hams F12 Nutrient Mix supplemented with 10% fetal bovine serum, 2mM L-glutamine and 15 mM HEPES. Confluent CHO-hV_(1A) cells were washedwith phosphate-buffered saline (PBS), harvested into ice cold PBS andcentrifuged at 1,000 rpm. Cell pellets were stored at −80° C. until use.Cell pellets were thawed on ice and homogenised in membrane preparationbuffer consisting of 50 mM Tris-HCl, pH 7.4, 5 mM MgCl₂ and supplementedwith a protease inhibitor cocktail, (Roche). The cell homogenate wascentrifuged at 1000 rpm, 10 min, 4° C. and the supernatant was removedand stored on ice. The remaining pellet was homogenised and centrifugedas before. The supernatants were pooled and centrifuged at 25,000×g for30 min at 4° C. The pellet was resuspended in freezing buffer consistingof 50 mM Tris-HCl, pH 7.4, 5 mM MgCl₂ and 20% glycerol and stored insmall aliquots at −80° C. until use. Protein concentration wasdetermined using Bradford reagent and BSA as a standard.

[0365] 1.2 V_(1A) Filter Bindin

[0366] Protein linearity followed by saturation binding studies wereperformed on each new batch of membrane. Membrane concentration waschosen that gave specific binding on the linear portion of the curve.Saturation binding studies were then performed using variousconcentrations of [³H]-arginine vasopressin, [³H]-AVP (0.05 nM-100 nM)and the K_(d) and B_(max) determined.

[0367] Compounds were tested for their effects on [³H]-AVP binding toCHO-hV_(1A) membranes, (³H-AVP; specific activity 65.5 Ci/mmol; NEN LifeSciences). Compounds were solubilised in dimethylsulfoxide (DMSO) anddiluted to working concentration of 10% DMSO with assay buffercontaining 50 mM Tris-HCL pH 7.4, 5 mM MgCl₂ and 0.05% BSA. 25 μlcompound and 25 μl [³H]-AVP, (final concentration at or below K_(d)determined for membrane batch, typically 0.5 nM-0.6 nM) were added to a96-well round bottom polypropylene plate. The binding reaction wasinitiated by the addition of 200 μl membrane and the plates were gentlyshaken for 60 min at room temperature. The reaction was terminated byrapid filtration using a Filtermate Cell Harvester (Packard Instruments)through a 96-well GF/B UniFilter Plate which had been presoaked in 0.5%polyethyleneimine to prevent peptide sticking. The filters were washedthree times with 1 ml ice cold wash buffer containing 50 mM Tris-HCL pH7.4 and 5 mM MgCl₂. The plates were dried and 50 μl Microscint-O(Packard instruments) was added to each well. The plates were sealed andcounted on a TopCount Microplate Scintillation Counter (PackardInstruments). Non-specific binding (NSB) was determined using 1 μMunlabelled d(CH2)5Tyr(Me)AVP([β-mercapto-β,β-cyclopentamethylenepropionyl,0-Me-Tyr²,Arg⁸]-vasopressin) (βMCPVP), (Sigma). The radioligand binding data was analysed using afour parameter logistic equation with the min forced to 0%. The slopewas free fitted and fell between −0.75 and −1.25 for valid curves.Specific binding was calculated by subtracting the mean NSB cpm from themean Total cpm. For test compounds the amount of ligand bound to thereceptor was expressed as % bound=(sample cpm—mean NSB cpm)/specificbinding cpm×100. The % bound was plotted against the concentration oftest compound and a sigmoidal curve was fitted. The inhibitorydissociation constant (K_(i)) was calculated using the Cheng-Prusoffequation: K_(i)=IC₅₀/(1+[L]/K_(d)) where [L] is the concentration ofligand present in the well and K_(d) is the dissociation constant of theradioligand obtained from Scatchard plot analysis.

[0368] 2.0 V₁A Functional Assay; Inhibition of AVP/V_(1A)-R MediatedCa²⁺ Mobilization by FLIPR (Fluorescent Imaging Plate Reader) (MolecularDevices)

[0369] Intracellular calcium release was measured in CHO-hV_(1A) cellsusing FLIPR, which allows the rapid detection of calcium followingreceptor activation. The CHO-hV_(1A) cell line was kindly provided undera licensing agreement by Marc Thibonnier, Dept. of Medicine, CaseWestern Reserve University School of Medicine, Cleveland, Ohio.CHO-V_(1A) cells were routinely maintained at 37° C. in humidifiedatmosphere with 5% CO₂ in DMEM/Hams F12 nutrient mix supplemented with10% fetal bovine serum, 2 mM L-glutamine, 15 mM HEPES and 400 μg/mlG418. On the afternoon before the assay cells were plated at a densityof 20,000 cells per well into black sterile 96-well plates with clearbottoms to allow cell inspection and fluorescence measurements from thebottom of each well. Wash buffer containing Dulbecco's phosphatebuffered saline (DPBS) and 2.5 mM probenecid and loading dye consistingof cell culture medium containing 4 μM Fluo-3-AM (dissolved in DMSO andpluronic acid),(Molecular Probes) and 2.5 mM probenecid was preparedfresh on the day of assay. Compounds were solubilised in DMSO anddiluted in assay buffer consisting of DPBS containing 1% DMSO, 0.1% BSAand 2.5 mM probenecid. The cells were incubated with 100 μl loading dyeper well for 1 hour at 37° C. in humidified atmosphere with 5% CO₂.After dye loading the cells were washed three times in 100 μl washbuffer using a Denley plate washer. 100 μl wash buffer was left in eachwell. Intracellular fluorescence was measured using FLIPR. Fluorescencereadings were obtained at 2 s intervals with 50 μl of the test compoundadded after 30 s. An additional 155 measurements at 2 s intervals werethen taken to detect any compound agonistic activity. 50 μl of argininevasopressin (AVP) was then added so that the final assay volume was 200μl. Further fluorescence readings were collected at 1 s intervals for120 s. Responses were measured as peak fluorescence intensity (FI). Forpharmacological characterization a basal FI was subtracted from eachfluorescence response. For AVP dose response curves, each response wasexpressed as a % of the response to the highest concentration of AVP inthat row. For IC₅₀ determinations , each response was expressed as a %of the response to AVP. IC50 values were converted to a modified K_(b)value using the Cheng-Prusoff equation which takes into account theagonist concentration, [A], the agonist EC₅₀ and the slope:K_(b)=IC₅₀/(2+[A]/A₅₀]^(n))^(1/n)−1 where [A] is the concentration ofAVP, A₅₀ is the EC₅₀ of AVP from the dose response curve and n=slope ofthe AVP dose response curve.

[0370] The compounds of the invention may have the advantage that theyare more potent, have a longer duration of action, have a broader rangeof activity, are more stable, have fewer side effects or are moreselective, or have other more useful properties than the compounds ofthe prior art.

[0371] Thus the invention provides:

[0372] (i) a compound of formula (I) or a pharmaceutically acceptablederivative thereof;

[0373] (ii) a process for the preparation of a compound of formula (I)or a pharmaceutically acceptable derivative thereof;

[0374] (iii) a pharmaceutical formulation including a compound offormula (I) or a pharmaceutically acceptable derivative thereof,together with a pharmaceutically acceptable excipients, diluent orcarrier;

[0375] (iv) a compound of formula (I) or a pharmaceutically acceptablederivative or composition thereof, for use as a medicament;

[0376] (v) the use of a compound of formula (I) or of a pharmaceuticallyacceptable derivative or composition thereof, for the manufacture of amedicament for the treatment of aggression, Alzheimer's disease,anorexia nervosa, anxiety, anxiety disorder, asthma, atherosclerosis,autism, cardiovascular disease (including angina, atherosclerosis,hypertension, heart failure, edema, hypernatremia), cataract, centralnervous system disease, cerebrovascular ischemia, cirrhosis, cognitivedisorder, Cushing's disease, depression, diabetes mellitus,dysmenorrhoea (primary and secondary), emesis (including motionsickness), endometriosis, gastrointestinal disease, glaucoma,gynaecological disease, heart disease, intrauterine growth retardation,inflammation (including rheumatoid arthritis), ischemia, ischemic heartdisease, lung tumor, micturition disorder, mittlesmerchz, neoplasm,nephrotoxicity, non-insulin dependent diabetes, obesity,obsessive/compulsive disorder, ocular hypertension, preclampsia,premature ejaculation, premature (preterm) labor, pulmonary disease,Raynaud's disease, renal disease, renal failure, male or female sexualdysfunction, septic shock, sleep disorder, spinal cord injury,thrombosis, urogenital tract infection or urolithiasis;

[0377] (vi) use as in (v) where the disease or disorder is anxiety,cardiovascular disease (including angina, atherosclerosis, hypertension,heart failure, edema, hypernatremia), dysmenorrhoea (primary andsecondary), endometriosis, emesis (including motion sickness),intrauterine growth retardation, inflammation (including rheumatoidarthritis), mittlesmerchz, preclampsia, premature ejaculation, premature(preterm) labor or Raynaud's disease;

[0378] (vii) use as in (v) where the disease or disorder isdysmenorrhoea (primary and secondary);

[0379] (viii) a method of treatment of a mammal to treat aggression,Alzheimer's disease, anorexia nervosa, anxiety, anxiety disorder,asthma, atherosclerosis, autism, cardiovascular disease (includingangina, atherosclerosis, hypertension, heart failure, edema,hypernatremia), cataract, central nervous system disease,cerebrovascular ischemia, cirrhosis, cognitive disorder, Cushing'sdisease, depression, diabetes mellitus, dysmenorrhoea (primary andsecondary), emesis (including motion sickness), endometriosis,gastrointestinal disease, glaucoma, gynaecological disease, heartdisease, intrauterine growth retardation, inflammation (includingrheumatoid arthritis), ischemia, ischemic heart disease, lung tumor,micturition disorder, mittlesmerchz, neoplasm, nephrotoxicity,non-insulin dependent diabetes, obesity, obsessive/compulsive disorder,ocular hypertension, preclampsia, premature ejaculation, premature(preterm) labor, pulmonary disease, Raynaud's disease, renal disease,renal failure, male or female sexual dysfunction, septic shock, sleepdisorder, spinal cord injury, thrombosis, urogenital tract infection orurolithiasis including treating said mammal with an effective amount ofa compound of formula (I) or with a pharmaceutically acceptablederivative or composition thereof;

[0380] (ix) a method as in (vii) where the disease or disorder isanxiety, cardiovascular disease (including angina, atherosclerosis,hypertension, heart failure, edema, hypernatremia), dysmenorrhoea(primary and secondary), endometriosis, emesis (including motionsickness), intrauterine growth retardation, inflammation (includingrheumatoid arthritis), mittlesmerchz, preclampsia, prematureejaculation, premature (preterm) labor or Raynaud's disease;

[0381] (x) a method as in (vii) where the disease or disorder isdysmenorrhoea (primary and secondary);

[0382] (xi) intermediates of the formulae (II), (III), (X), (XV),(XXIV), and (XXV);

[0383] (xii) use of a combination of a compound of formula (I) with anoral contraceptive for treating dysmenorrhoea (primary and/orsecondary);

[0384] (xiii) use of a combination of a compound of formula (I) with aPDE5 inhibitor for treating dysmenorrhoea (primary and/or secondary);

[0385] (xiv) use of a combination of a compound of formula (I) with anNO donor for treating dysmenorrhoea (primary and/or secondary);

[0386] (xv) use of a combination of a compound of formula (I) withL-arginine for treating dysmenorrhoea (primary and/or secondary);

[0387] (xvi) use of a combination of a compound of formula (I) with aCOX inhibitor for treating dysmenorrhoea (primary and/or secondary).

[0388] The invention is illustrated by the following preparations andexamples:

Preparation 1: 3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acidhydrazide

[0389]

[0390] 3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethylester (1 g, 4.3 mmol)(see reference Farmaco, 1993, 48(10), 1439) wasdissolved in methanol (20 ml) containing hydrazine hydrate (620 μl, 20mmol) and was heated under reflux for 18 hours. The mixture was cooledto room temperature and evaporated under reduced pressure. The solidformed was triturated with propan-2-ol to give the title compound as awhite solid (493 mg).

[0391] APCl MS m/z 221 [M+H]⁺

Preparation 1b: 3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester

[0392]

[0393] Potassium carbonate (52.5 g, 0.379 mol) was charged to a stirredsolution of 2-Bromopyridine (60 g, 0.379 mol) and Ethylisonipecotate(59.7 g, 0.379 mol), at an ambient temperature before heating to 120° C.for 24 hours. The mixture was cooled to room temperature and propan-2-olcharged to the solution. The reaction mixture was then filtered andtelescoped into preparation 1c.

Preparation 1c: 3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid hydrazide

[0394]

[0395] Hydrazine hydrate (61.4 ml, 1.265 mol) was charged to apropan-2-ol solution of3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester(0.253 mol, 5 ml/g)(see reference Farmaco, 1993, 48(10), 1439), beforeheating under reflux for 18 hours. The mixture was cooled to roomtemperature and then to 10° C. and the product, a white solid, wascollected by filtration (44.5 g).

[0396] APCl MS m/z 221 [M+H]⁺

Preparation 2: 1-Pyrimidin-2-yl-piperidine-4-carboxylic acid hydrazide

[0397]

[0398] The title compound was obtained from1-Pyrimidin-2-yl-piperidine-4-carboxylic acid ethyl ester (see Farmaco,1993, 48(10), 1439) in 91% yield following the procedure described inpreparation 1.

[0399] APCl MS m/z 222 [M+H]⁺

Preparation 3: 3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acidN′-(2-chloro-acetyl)-hydrazide

[0400]

[0401] The hydrazide of Preparation 1 (23.6 g, 0.11 mol) was suspendedin dichloromethane (500 ml) and 4-methylmorpholine (17.7 ml, 0.16 mol)was added. The mixture was cooled using an ice bath and chloroacetylchloride (12.8 ml, 0.16 mol) was added dropwise. The reaction was warmedto room temperature and was stirred for 3 hours. The solid formed wasisolated by filtration, washed with dichloromethane and diethyl ether,and dried under vacuum to give the title compound (20.4 g).

[0402] LCMS: m/z ES⁺ 297 [M+H]⁺

Preparation 3b: 3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid N′-(2-chloro-acetyl)-hydrazide

[0403]

[0404] The hydrazide of Preparation 1c (5.0 g, 23 mmol) was suspended indichloromethane (100 ml) and 4-methylmorpholine (3.75 ml, 34 mmol) wasadded. The mixture was cooled using an ice bath and chloroacetylchloride (1.9 ml, 24 mmol) was added dropwise. The reaction was warmedto room temperature and was stirred for 3 hours. The solid formed wasisolated by filtration, washed with dichloromethane, and dried undervacuum to give the title compound (2.2 g).

[0405] LCMS: m/z ES⁺ 297 [M+H]⁺

Preparation 4: 1-Pyrimidin-2-yl-piperidine-4-carboxylic acidN′-(2-chloro-acetyl)-hydrazide

[0406]

[0407] The title compound was prepared from the hydrazide of preparation2 and chloroacetyl chloride, in 96% yield, using the procedure describedin preparation 3.

[0408] APCl MS m/z 298 [M+H]⁺

Preparation 5:4-(5-Chloromethyl-[1,3,4]oxadiazol-2-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

[0409]

[0410] The hydrazide of Preparation 3 (20.4 g, 69 mmol) was suspended inphosphorus oxychloride (150 ml) at 100° C. for 4 hours. The mixture wascooled and the solvent was evaporated under reduced pressure. Theresidue was dissolved in ethyl acetate and was added to water. Theaqueous layer was basified by addition of solid sodium hydrogencarbonate and the phases were separated. The aqueous phase was extractedwith ethyl acetate (×2) and the combined organic layers were dried overmagnesium sulphate and evaporated under reduced pressure. The materialisolated was triturated with diethyl ether to give the title compound asa beige solid (15 g).

[0411]¹H NMR (400 MHz, CD₃OD): δ 1.91 (m, 2H), 2.19 (m, 2H), 3.14 (m,2H), 3.30 (m, 1H), 4.29 (m, 2H), 4.86 (s, 2H), 6.69 (m, 1H), 6.89 (d,1H), 7.58 (m, 1H), 8.08 (d, 1H)

Preparation 5b:4-(5-Chloromethyl-[1,3,4]oxadiazol-2-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

[0412]

[0413] The hydrazide of Preparation 3 (50.0 g, 169 mmol) was suspendedin acetonitrile (250 ml) and cooled using an ice bath.Trifluoromethanesulfonic anhydride (29.9 ml, 177 mmol) was addeddropwise at T<15° C. The reaction was warmed to room temperature andstirred for 16 hours. The reaction was cooled using an ice bath and asolution of sodium hydrogen carbonate (29.8 g, 354 mmol) in water (250ml) was added dropwise. Dichloromethane (250 ml) was added and thephases were separated. The organic containing product phase was used inpreparation 14b.

[0414]¹H NMR (400 MHz, CD₃OD): δ 1.91 (m, 2H), 2.19 (m, 2H), 3.14 (m,2H), 3.30 (m, 1H), 4.29 (m, 2H), 4.86 (s, 2H), 6.69 (m, 1H), 6.89 (d,1H), 7.58 (m, 1H), 8.08 (d, 1H)

Preparation 6:2-[4-(5-Chloromethyl-[1,3,4]oxadiazol-2-yl)-piperidin-1-yl]-pyrimidine

[0415]

[0416] The title compound was prepared from the hydrazide of preparation4, in 84% yield, using the procedure described in preparation 5.

[0417] APCl MS m/z 280 [M+H]⁺

[0418]¹H NMR (400 MHz, CDCl₃): δ 1.91 (m, 2H), 2.19 (m, 2H), 3.14 (m,3H), 4.65 (s, 2H), 4.86 (m, 2H), 6.49 (m, 1H), 6.89 (d, 1H), 8.35 (d,1H)

Preparation 7: (2-Amino-5-methoxy-phenyl)-methanol

[0419]

[0420] 2-Amino-5-methoxy-benzoic acid (2.0 g, 12 mmol) intetrahydrofuran (20 ml) was added dropwise to an ice cooled 1 molarsolution of lithium aluminium hydride (14.4 ml) in tetrahydrofuran andstirred at 5°0 C. for 2 hours. Water (0.5 ml) was added dropwise,followed by 2 molar aqueous sodium hydroxide solution (0.5 ml). Theresulting emulsion was dried over magnesium sulphate, then filtered andevaporated under reduced pressure to give the title compound as a yellowsolid (766 mg).

[0421] APCl MS m/z 154 [M+H]⁺

[0422]¹H NMR (400 MHz, CD₃OD): δ 3.70 (s, 3H), 4.55 (s, 2H), 6.65-6.78(m, 3H)

Preparation 8: (2-Amino-6-chloro-phenyl)-methanol

[0423]

[0424] The title compound was prepared from 2-Amino-6-chloro-benzoicacid, in 69% yield as an off-white solid, following the proceduredescribed in preparation 7.

[0425] APCl MS m/z 158 [M+H]⁺

[0426]¹H NMR (400 MHz, CDCl₃): δ 4.85 (s, 2H), 6.60 (d, 1H), 6.80 (d,1H), 7.00 (t, 1H)

Preparation 9: (2-Amino-4-chloro-phenyl)-methanol

[0427]

[0428] The title compound was prepared from 2-Amino-4-chloro-benzoicacid, in 48% yield as an off-white solid, following the proceduredescribed in preparation 7.

[0429] APCl MS m/z 170 [MNa]⁺

[0430]¹H NMR (400 MHz, CD₃OD): δ 4.55 (s, 2H), 6.60 (d, 1H), 6.70 (d,1H), 7.00 (d, 1H)

Preparation 10: 2-Aminomethyl-4-chloro-phenylamine

[0431]

[0432] 2-Amino-5-chloro-benzonitrile (9.0 g, 59 mmol) in tetrahydrofuran(100 ml) was added dropwise to an ice cooled 1 molar solution of lithiumaluminium hydride (100 ml) in tetrahydrofuran and the reaction mixturewas stirred at room temperature for 18 hours. Water (10 ml) was addeddropwise. The resulting emulsion was dried over magnesium sulphate,filtered and evaporated under reduced pressure to give the titlecompound as a white solid (4.56 g).

[0433]¹H NMR (400 MHz, CDCl₃): δ 3.85 (s, 2H), 4.50 (s, 2H), 6.60 (d,1H), 7.05 (m, 2H)

Preparation 11: Acetic acid 2-(2-acetylamino-5-chloro-phenyl)-ethylester

[0434]

[0435] A solution of chlorine in glacial acetic acid (0.98M, 30 ml) wasadded dropwise to a solution of N-[2-(2-Hydroxy-ethyl)-phenyl]-acetamide(5.0 g, 27.9 mmol)(see reference Biochemistry 1979, 18(5), 860) inglacial acetic acid (50 ml) and the mixture was stirred at roomtemperature for 20 hours. The glacial acetic acid was removed underreduced pressure. The resulting oil was triturated with diethyl ether togive the title compound (3.3 g) as a pale yellow solid after filtration.

[0436] APCl MS m/z 256, [MH]⁺, 278 [MNa]⁺

[0437]¹H NMR (400 MHz, CDCl₃): δ 2.13 (s, 3H), 2.26 (s, 3H), 2.87 (t,2H), 4.13 (t, 2H), 7.11 (d, 1H), 7.23 (dd, 1H), 8.05 (d, 1H), 8.27 (s,1H).

Preparation 12: 2-(2-Amino-5-chloro-phenyl)-ethanol

[0438]

[0439] The compound from preparation 11 was suspended in 2 molar aqueoushydrochloric acid (20 ml) and heated to 100° C. for 4 hours. Thesolution was allowed to cool, made basic (pH 9) with 0.880 aqueousammonia and partitioned with ethyl acetate (50 ml). The organic layerwas washed with water and saturated brine, and dried over magnesiumsulphate. The solution was filtered and then evaporated under reducedpressure. The residue was purified by chromatography on silica gel usingmethanol and ammonium hydroxide in dichloromethane as eluant (5:0.5:95)to give the title compound as a brown oil (0.43 g).

[0440] APCl MS m/z 172, [MH]⁺

[0441]¹H NMR (400 MHz, CD₃OD): δ 2.64 (t, 2H), 3.69(t, 2H), 6.61 (d,1H), 6.87 (dd, 1H), 6.93 (d, 1H).

Preparation 13:2-({[5-(3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[1,3,4]oxadiazol-2-ylmethyl]-amino}-methyl)-phenylamine

[0442]

[0443] A solution of 2-Aminomethyl-phenylamine (2.2 g, 17.9 mmol) intetrahydrofuran (50 ml) was added to a solution of the oxadiazole ofpreparation 5 (2.0 g, 7.18 mmol) in tetrahydrofuran (50 ml) and themixture was heated to 50° C. for 18 hours. The reaction mixture wasevaporated under reduced pressure and the residue was purified bychromatography on silica gel using methanol and ammonium hydroxide indichloromethane as eluant (5:0.5:95), to give the title compound as apale yellow gum (2.6 g).

[0444] APCl MS m/z 365 [MH]⁺, 387 [MNa]⁺

[0445]¹H NMR (400 MHz, CDCl₃): δ 1.94 (m, 2H), 2.18(m, 2H), 3.14 (m,3H), 3.88(s, 2H), 4.00 (s, 2H), 4.31 (m, 2H), 6.60-6.75 (m, 4H), 7.02(d, 1H), 7.12 (t, 1H), 7.48 (t, 1H), 8.20 (d, 1H).

Preparation 14:4-Chloro-2-({[5-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[1,3,4]oxadiazol-2-ylmethyl]-amino}-methyl)-phenylamine

[0446]

[0447] A solution of the amine of preparation 10 (6.4 g, 41 mmol) intetrahydrofuran (50 ml) was added to a solution of the oxadiazole ofpreparation 5 (4.56 g, 16 mmol) in tetrahydrofuran (50 ml) and themixture was heated to 50° C. for 18 hours. The reaction mixture wasevaporated under reduced pressure and the residue was purified bychromatography on silica gel using methanol in dichloromethane as eluant(5:95), to give the title compound as a white solid (4.65 g).

[0448] APCl MS m/z 399 [MH]⁺

[0449]¹H NMR (400 MHz, CDCl₃): δ 1.95 (m, 2H), 2.20(m, 2H), 3.10 (m,2H), 3.20 (m, 1H), 3.80(s, 2H), 4.00 (s, 2H), 4.30 (m, 2H), 6.60 (m,1H), 6.65 (t, 1H), 6.70 (d, 1H), 7.00 (s, 1H), 7.05 (d, 1H), 7.50 (t,1H), 8.20 (d, 1H)

Preparation 14b:4-Chloro-2-({[5-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[1,3,4]oxadiazol-2-ylmethyl]-amino}-methyl)-phenylamine

[0450]

[0451] The acetonitrile/dichloromethane solution of the oxadiazole frompreparation 5b was distilled, the residue placed in acetonitrile, andthen heated at reflux with sodium hydrogen carbonate (14.9 g, 177 mmol)and the amine from preparation 10 (39.7 g, 253 mmol) for 5 hours. Themixture was cooled and water (250 ml) and dichloromethane (1500 ml) wasadded. The phases were separated and the organic phase distilled andreplaced with ethyl acetate. The resulting precipitate was isolated byfiltration to afford the title compound as a yellow solid (32.8 g)

[0452] APCl MS m/z 280 [M+H]⁺

[0453]¹H NMR (400 MHz, CDCl₃): δ 1.91 (m, 2H), 2.19 (m, 2H), 3.14 (m,3H), 4.65 (s, 2H), 4.86 (m, 2H), 6.49 (m, 1H), 6.89 (d, 1H), 8.35 (d,1H)

Preparation 15:4-Chloro-2-({[5-(1-pyrimidin-2-yl-piperidin-4-yl)-[1,3,4]oxadiazol-2-ylmethyl]-amino}-methyl)-phenylamine

[0454]

[0455] A solution of the amine of preparation 10 (4.12 g, 26 mmol) intetrahydrofuran (50 ml) was added to a solution of the oxadiazole ofpreparation 6 (2.95 g, 11 mmol) in tetrahydrofuran (50 ml) and heated to50° C. for 18 hours. The reaction mixture was evaporated under reducedpressure and the residue purified by chromatography on silica gel usingethyl acetate as eluant to give the title compound as an off-white solid(2.34 g).

[0456] APCl MS m/z 400 [MH]⁺

[0457]¹H NMR (400 MHz, CDCl₃): δ 1.80 (m, 2H), 2.20 (m, 2H), 3.20 (m,3H), 3.80 (s, 2H), 4.00 (s, 2H), 4.75 (m, 2H), 6.50 (t, 1H), 6.60 (d,1H), 7.00 (d, 1H), 7.05 (d, 1H), 8.35 (d, 2H).

Preparation 16:2-[5-(3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[1,3,4]oxadiazol-2ylmethoxymethyl]-phenylamine

[0458]

[0459] A solution of (2-Amino-phenyl)-methanol (996 mg, 8 mmol) intetrahydrofuran (5 ml) was added dropwise to an ice cooled suspension ofsodium hydride (60% in mineral oil, 324 mg, 8.1 mmol) in tetrahydrofuran(5 ml) and stirred for 0.5 hour. A solution of the oxadiazole ofpreparation 5 (750 mg, 2.69 mmol) in tetrahydrofuran (5 ml) was addeddropwise and the mixture stirred at room temperature for 3 hours. Ethylacetate (50 ml) was added and the solution was extracted with water (25ml). The aqueous solution was washed with ethyl acetate (2×20 ml). Thecombined organic layers were dried over magnesium sulphate andevaporated under reduced pressure. The residue was purified bychromatography on silica gel using a gradient of ethyl acetate inpentane as eluant (2:1 to 100:0) to give the title compound (300 mg) asa white solid.

[0460] APCl MS m/z 366 [MH]⁺

[0461]¹H NMR (400 MHz, CDCl₃): δ 1.90 (m, 2H), 2.20 (m, 2H), 3.10 (m,2H), 3.20 (m, 1H), 4.20 (s, 2H), 4.35 (m, 2H), 4.64 (s, 2H), 4.66 (s,2H), 6.65 (m, 4H), 7.05 (d, 1H), 7.15 (t, 1H), 7.50 (t, 1H), 8.20 (d,1H).

Preparation 17:3-Chloro-2-[5-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[1,3,4]oxadiazol-2-ylmethoxymethyl]-phenylamine

[0462]

[0463] The title compound was prepared from the alcohol of preparation 8and the oxadiazole of preparation 5, in 55% yield, using the proceduredescribed in preparation 16.

[0464] APCl MS m/z 400 [MH]⁺

[0465]¹H NMR (400 MHz, CDCl₃): δ 1.95 (m, 2H), 2.20 (m, 2H), 3.05 (m,2H), 3.20 (m, 1H), 4.30 (m, 2H), 4.40 (s, 2H), 4.70 (s, 2H), 4.90 (s,2H), 6.55 (d, 1H), 6.60 (m, 1H), 6.70 (d, 1H), 6.75 (d, 1H), 7.00 (t,1H), 7.15 (t, 1H), 7.45 (t, 1H), 8.20 (d, 1H).

Preparation 18:5-Chloro-2-[5-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[1,3,4]oxadiazol-2-ylmethoxymethyl]-phenylamine

[0466]

[0467] The title compound was prepared from the alcohol of preparation 9and the oxadiazole of preparation 5, in 42% yield, using the proceduredescribed in preparation 16.

[0468] APCl MS m/z 400 [MH]⁺, 422 [MNa]⁺

[0469]¹H NMR (400 MHz, CDCl₃): δ 1.90 (m, 2H), 2.20 (m, 2H), 3.10 (m,3H), 4.30 (m, 4H), 4.60 (s, 2H), 4.65 (s, 2H), 6.75 (m, 4H), 7.00 (d,1H), 7.45 (t, 1H), 8.20 (d, 1H).

Preparation 19: 4-Methoxy-2-[5-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[1,3,4]oxadiazol-2-ylmethoxymethyl]-phenylamine

[0470]

[0471] The title compound was prepared from the alcohol of preparation 7and the oxadiazole of preparation 5, in 53% yield, using the proceduredescribed in preparation 16.

[0472] APCl MS m/z 396 [MH]⁺, 418 [MNa]⁺

[0473]¹H NMR (400 MHz, CDCl₃): δ 1.95 (m, 2H),.2.20 (m, 2H), 3.10 (m,3H), 3.75 (s, 3H), 4.60 (s, 2H), 4.65 (s, 2H), 6.70 (m, 5H), 7.45 (t,1H), 8.20 (d, 1H).

Preparation 20:4-Chloro-2-[5-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[1,3,4]oxadiazol-2-ylmethoxymethyl]-phenylamine

[0474]

[0475] The title compound was prepared from(2-Amino-5-chloro-phenyl)-methanol and the oxadiazole of preparation 5,in 61% yield, using the procedure described in preparation 16.

[0476] APCl MS m/z 400 [MH]⁺

[0477]¹H NMR (400 MHz, CDCl₃): δ 1.95 (m, 2H), 2.20 (m, 2H), 3.10 (m,2H), 3.20 (m, 1H), 4.20 (s, 2H), 4.35 (m, 2H), 4.60 (s, 2H), 4.70 (s,2H), 6.60 (m, 2H), 6.70 (d, 1H), 7.10 (m, 2H), 7.45 (t, 1H), 8.20 (d,1H).

Preparation 21:2-{2-[5-(3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[1,3,4]oxadiazol-2-ylmethoxy]-ethyl}-phenylamine

[0478]

[0479] The title compound was prepared from 2-(2-Amino-phenyl)-ethanoland the oxadiazole of preparation 5, in 66% yield, using the proceduredescribed in preparation 16.

[0480] APCl MS m/z 380 [MH]⁺

[0481]¹H NMR (400 MHz, CDCl₃): δ 1.95 (m, 2H), 2.15 (m, 2H), 2.80 (t,2H), 3.10 (m, 3H), 3.80 (m, 4H), 4.30 (m, 2H), 4.65 (s, 2H), 6.70 (m,4H), 7.00 (m, 2H), 7.50 (t, 1H), 8.20 (d, 1H).

Preparation 22:4-Chloro-2-{2-[5-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[1,3,4]oxadiazol-2-ylmethoxy]-ethyl}-phenylamine

[0482]

[0483] The title compound was prepared from the alcohol of preparation12 and the oxadiazole of preparation 5, in 52% yield, using theprocedure described in preparation 16.

[0484] APCl MS m/z 414 [MH]⁺

[0485]¹H NMR (400 MHz, CDCl₃): δ 1.92 (m, 2H), 2.15 (m, 2H), 2.77 (t,2H), 3.10 (m, 3H), 3.79 (t, 2H), 4.28 (m, 2H), 4.66 (s, 2H), 6.58 (d,1H), 6.62 (d, 1H), 6.71 (d, 1H), 6.97 (m, 2H), 7.49 (t, 1H), 8.20 (d,1H).

Preparation 23:4-Chloro-2-[5-(1-pyrimidin-2-yl-piperidin-4-yl)-[1,3,4]oxadiazol-2-ylmethoxymethyl]-phenylamine

[0486]

[0487] A solution of (2-Amino-5-chloro-phenyl)-methanol (850 mg, 5.4mmol) in tetrahydrofuran (10 ml) was added dropwise to an ice cooledsuspension of sodium hydride (60% in mineral oil, 215 mg, 5.4 mmol) intetrahydrofuran (5 ml) and stirred for 1 hour. A solution of theoxadiazole of preparation 6 (500 mg, 1.79 mmol) in tetrahydrofuran (5ml) was added dropwise and the mixture stirred at room temperature for 1hour. Dichloromethane (50 ml) was added and the solution was extractedwith water (25 ml). The aqueous solution was washed with dichloromethane(2×20 ml). The combined organic layers were dried over magnesiumsulphate and evaporated under reduced pressure. The residue was purifiedby chromatography on silica gel using diethyl ether followed by ethylacetate as eluant to give, after trituration with diethyl ether, thetitle compound (320 mg) as a white solid.

[0488] APCl MS m/z 401 [MH]⁺

[0489]¹H NMR (400 MHz, CDCl₃): δ 1.92 (m, 2H), 2.19 (m, 2H), 3.24 (m,3H), 4.60 (s, 2H), 4.68 (s, 2H), 4.75 (m, 2H), 6.57 (m, 1H), 6.63 (d,1H), 7.08 (m, 2H), 8.37 (d, 2H).

Preparation 24:2-{2-[5-(1-Pyrimidin-2-yl-piperidin-4-yl)-[1,3,4]oxadiazol-2-ylmethoxy]-ethyl}-phenylamine

[0490]

[0491] The title compound was prepared from 2-(2-Amino-phenyl)-ethanoland the oxadiazole of preparation 6, in 54% yield, using the proceduredescribed in preparation 23.

[0492] APCl MS m/z 381 [MH]⁺

[0493]¹H NMR (400 MHz, CDCl₃): δ 1.85 (m, 2H), 2.15 (m, 2H), 2.88 (m,2H), 3.18 (m, 3H), 1H), 3.80 (t, 2H), 4.68 (s, 2H), 4.74 (m, 2H), 6.51(m, 1H), 6.80 (m, 2H), 7.08 (m, 2H), 8.37 (d, 2H).

Preparation 25:4-[N′-(2-Chloro-acetyl)-hydrazinocarbonyl]-piperidine-1-carboxylic acidtert-butyl ester

[0494]

[0495] 4-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester(see reference WO 9703986 A1 19970206)(25 g, 103 mmol) was dissolved indichloromethane (300 ml) and 4-methylmorpholine (12.5 ml, 113 mmol) wasadded. The mixture was cooled using an ice bath and chloroacetylchloride (8.2 ml, 103 mmol) was added dropwise. The reaction was warmedto room temperature and was stirred for 4 hours. The reaction mixturewas partitioned with aqueous sodium hydrogen carbonate solution, driedover magnesium sulphate, filtered and the filtrate evaporated to givethe title compound as an off-white solid (29.6 g).

[0496] APCl MS m/z 318 [M-H]⁺

[0497] Found; C, 48.01; H, 6.91; N, 12.85; C₁₃H₂₂N₃O₄Cl 0.3 H₂Orequires; C, 48.02; H, 7.01; N, 12.92%.

Preparation 26:4-(5-Chloromethyl-[1,3,4]oxadiazol-2-yl)-piperidine-1-carboxylic acidtert-butyl ester

[0498]

[0499] The hydrazide of preparation 25 (5.0 g, 15.6 mmol) was suspendedin dichloromethane (200 ml) and pyridine (6.4 ml, 78 mmol) added beforecooling the mixture to 10° C. Trifluoroacetic anhydride (6.6 ml, 39mmol) was added dropwise over 15 minutes and then stirred at roomtemperature for 3 hours. The reaction mixture was partitioned with water(50 ml) and the organic layer dried over magnesium sulphate. The mixturewas filtered and the filtrate evaporated under reduced pressure. Theresidue was purified by chromatography on silica gel using methanol indichloromethane as eluant (2:98) to give the title compound as a whitesolid (2.95 g).

[0500]¹H NMR (400 MHz, CD₃OD): δ 1.45 (s, 9H), 1.74 (m, 2H), 2.19 (m,2H), 3.04 (m, 2H), 3.24 (m, 1H), 4.09 (m, 2H), 4.85 (s, 2H)

Preparation 27:4-[5-(2-Amino-5-chloro-benzyloxymethyl)-[1,3,4]oxadiazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

[0501]

[0502] A solution of (2-Amino-5-chloro-phenyl)-methanol (1 g, 6.4 mmol)in tetrahydrofuran (10 ml) was added dropwise to an ice cooledsuspension of sodium hydride (60% in mineral oil, 215 mg, 5.4 mmol) intetrahydrofuran (5 ml) and stirred for 1 hour. A solution of theoxadiazole of preparation 26 (1 g, 5.3 mmol) in tetrahydrofuran (5 ml)was added dropwise and the mixture stirred at room temperature for 2hours. The reaction mixture was partitioned between dichloromethane (50ml) and sodium hydrogen carbonate solution (25 ml). The aqueous solutionwas washed with dichloromethane (2×20 ml). The combined organic layerswere dried over magnesium sulphate and evaporated under reducedpressure. The residue was purified by chromatography on silica gel usingmethanol in dichloromethane (5:95) as eluant to give the title compound(1.3 g) as a yellow solid.

[0503] APCl MS m/z 423 [MH]⁺, 323 [M-Boc]⁺

[0504]¹H NMR (400 MHz, CDCl₃): δ 1.47 (s, 9H), 1.81 (m, 2H), 2.07 (m,2H), 2.96 (m, 2H), 3.08 (m, 1H), 4.12 (m, 2H), 4.23 (s, 2H), 4.58 (s,2H), 4.68 (s, 2H), 6.62 (d, 1H), 7.07 (s, 1H), 7.12 (d, 1H).

Preparation 28:4-(8-Chloro-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulen-1-yl)-piperidine-1-carboxylicacid tert-butyl ester

[0505]

[0506] Toluene-4-sulfonic acid (80 mg, 0.46 mmol) was added to asolution of the oxadiazole of preparation 27 (1.28 g, 3.0 mmol) inxylene and heated to 140° C. for 18 hours. The xylene was removed underreduced pressure. The residue was partitioned between dichloromethane(100 ml) and sodium hydrogen carbonate solution (25 ml). The aqueoussolution was washed with dichloromethane (2×20 ml). The combined organiclayers were dried over magnesium sulphate and evaporated under reducedpressure. The residue was purified by chromatography on silica gel usingmethanol and ammonium hydroxide in dichloromethane (5:0.5:95) as eluantto give the title compound (730 mg) as a pale yellow foam.

[0507] APCl MS m/z 405 [MH]⁺, 305 [M-Boc]⁺

[0508]¹H NMR (400 MHz, CDCl₃): δ 1.43 (s, 9H), 1.85 (m, 2H), 1.96 (m,2H), 2.92 (m, 2H), 3.08 (m, 1H), 4.18 (m, 2H), 4.40 (s, 2H), 4.66 (s,2H), 7.36 (d, 1H), 7.58 (m, 2H).

[0509] Found; C, 57.98; H, 6.17; N, 13.40; C₂₀H₂₅N₄O₃Cl 0.5H₂O requires;C, 58.04; H, 6.33; N, 13.54%.

Preparation 29:8-Chloro-1-piperidin-4-yl-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulene

[0510]

[0511] The triazole of preparation 28 (700 mg, 1.73 mmol) was dissolvedin 1,4-dioxan (6 ml) and hydrochloric acid (4M in 1,4-dioxane, 12 ml)added. The reaction mixture was stirred at room temperature for 4 hours.The 1,4-dioxane was removed under reduced pressure.

[0512] The residue was partitioned between dichloromethane (100 ml) andsodium hydrogen carbonate solution (25 ml). The aqueous solution waswashed with dichloromethane (2×20 ml). The combined organic layers weredried over magnesium sulphate and evaporated under reduced pressure togive the title compound (410 mg) as a pale yellow foam.

[0513] APCl MS m/z 305 [MH]⁺

[0514]¹H NMR (400 MHz, CD₃OD): δ 1.83 (m, 4H), 2.65 (t, 2H), 3.09 (m,2H), 3.24 (m, 1H), 4.41 (s, 2H), 4.58 (s, 2H), 7.58 (m, 3H).

Preparation 30: (2-Amino-5-fluoro-phenyl)-methanol

[0515]

[0516] The title compound was prepared from 2-Amino-5-fluoro-benzoicacid, in 81% yield as an off-white solid, following the proceduredescribed in preparation 7.

[0517] APCl MS m/z 142 [M+H]⁺

[0518]¹H NMR (400 MHz, CDCl₃): δ 4.60 (s, 2H), 6.60 (dd, 1H), 6.77-6.86(m, 2H)

Preparation 31:4-Fluoro-2-[5-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[1,3,4]oxadiazol-2-ylmethoxymethyl]-phenylamine

[0519]

[0520] The title compound was prepared from the alcohol of preparation30 and the oxadiazole of preparation 5, in 60% yield, using theprocedure described in preparation 16.

[0521] APCl MS m/z 384 [M+H]⁺

[0522]¹H NMR (400 MHz, CDCl₃): δ 1.95 (dq, 2H), 2.18 (d, 2H), 3.06-3.21(m, 3H), 4.33 (td, 2H), 4.60 (s, 2H), 4.70 (s, 2H), 6.58-.6.67 (m, 2H),6.73 (d, 1H), 6.80-6.90 (m, 2H), 7.52 (t, 1H), 8.19 (d, 1H).

Preparation 32: (2-Amino-4,5-difluoro-phenyl)-methanol

[0523]

[0524] The title compound was prepared from 2-Amino-4,5-difluoro-benzoicacid, in 86% yield as a yellow solid, following the procedure describedin preparation 7.

[0525] APCl MS m/z 142 [M+H-H₂O]⁺, 160 [M+H]⁺

[0526]¹H NMR (400 MHz, CDCl₃): δ 4.10 (bs, 2H), 4.58 (s, 2H), 6.48 (dd,1H), 6.92 (dd, 1H)

Preparation 33:4,5-difluoro-2-[5-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[1,3,4]oxadiazol-2-ylmethoxymethyl]-phenylamine

[0527]

[0528] The title compound was prepared from the alcohol of preparation32 and the oxadiazole of preparation 5, in 50% yield, using theprocedure described in preparation 16.

[0529] APCl MS m/z 402 [M+H]⁺

[0530]¹H NMR (400 MHz, CDCl₃): δ 1.94 (dq, 2H), 2.09 (bd, 1H), 3.09 (bt,2H), 3.18 (m, 1H), 4.20 (bs, 2H), 4.33 (td, 2H), 4.54 (s, 2H), 4.68 (s,2H), 6.47 (dd, 1H), 6.64 (t, 1H), 6.72 (d, 1H)6.92 (dd, 1H), 7.52 (t,1H), 8.19, (d, 1H)

Preparation 34: 2-Amino-5-trifluoromethoxy-benzoic acid

[0531]

[0532] 5-Trifluoromethoxy-1H-indole-2,3-dione (3.48 g, 15.0 mmol) wasdissolved in 2N aqueous sodium hydroxide (90 ml) and cooled to 17° C.before adding 30% aqueous hydrogen peroxide solution (2.75 ml, 27 mmol)dropwise over 20 minutes. The mixture was stirred at room temperaturefor 1 hour before adding concentrated hydrochloric acid (7 ml). Theresulting brown precipitate was filtered off and dried in vacuo at 50°C. for 66 hours to give the title compound (1.83 g) as a brown solid.

[0533] APCl MS m/z 220 [M−H]⁺

[0534]¹H NMR (400 MHz, DMSO): δ 6.80 (d, 1H) 7.24 (dd, 1H), 7.53 (d, 1H)

Preparation 35: (2-Amino-5-trifluoromethoxy-phenyl)-methanol

[0535]

[0536] The title compound was prepared from the acid of preparation 34,in 62% yield as a white solid, following the procedure described inpreparation 7.

[0537] APCl MS m/z 206 [M−H]⁺

[0538]¹H NMR (400 MHz, CDCl₃): δ 4.85 (s, 2H), 6.67 (d, 1H), 6.92-7.00(m, 2H)

Preparation 36:2-[5-(3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[1,3,4]oxadiazol-2-ylmethoxymethyl]-4-trifluoromethoxy-phenylamine

[0539]

[0540] The title compound was prepared from the alcohol of preparation35 and the oxadiazole of preparation 5, in 28% yield, using theprocedure described in preparation 16.

[0541] APCl MS m/z 450 [M+H]⁺

[0542]¹H NMR (400 MHz, CDCl₃): δ 1.94 (dq, 2H), 2.16 (bd, 1H), 3.09 (t,2H), 3.17 (m, 1H), 4.37 (bd, 2H), 4.60 (s, 2H), 4.67 (s, 2H), 6.60-6.66(m, 2H), 6.70 (d, 1H), 6.95-7.07 (m, 2H), 7.49 (t, 1H) 8.19, (d, 1H)

Preparation 37:4-Methyl-2-[5-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[1,3,4]oxadiazol-2-ylmethoxymethyl]-phenylamine

[0543]

[0544] The title compound was prepared from(2-Amino-5-methyl-phenyl)-methanol (see Arch. Pharm. (1929), 583) andthe oxadiazole of preparation 5, in 38% yield, using the proceduredescribed in preparation 16.

[0545] APCl MS m/z 380 [M+H]⁺

[0546]¹H NMR (400 MHz, CDCl₃): δ 1.92 (dq, 2H), 2.16 (bd, 2H), 2.19 (s,3H), 3.09 (t, 2H), 317 (m, 1H), 4.37 (bd, 2H), 4.60 (s, 2H), 4.67 (s,2H), 6.64 (m, 2H), 6.85 (m, 3H), 7.58 (t, 1H) 8.09, (d, 1H)

Preparation 38: N-[2-(2-Acetylamino-ethyl)-phenyl]-acetamide

[0547]

[0548] A solution of acetic anhydride (9.6 ml, 101 mmol) indichloromethane (50 ml) was added dropwise to a solution of2-(2-Amino-ethyl)-phenylamine (see JACS 99, (1977), 5716)(8.0 g, 46mmol) and triethylamine (8.4 ml, 60 mmol) in dichloromethane (200 ml).The mixture was stirred at room temperature for 18 hours beforepartitioning with water (100 ml). The organic layer was washed with asaturated solution of brine (50 ml), dried over magnesium sulphate andevaporated under reduced pressure. The residue was purified bychromatography on silica gel using methanol and ammonium hydroxide indichloromethane (5:0.5:95) as eluant to give the title compound (4.1 g)as an off-white solid.

[0549] APCl MS m/z 221 [M+H]⁺

[0550]¹H NMR (400 MHz, CDCl₃): δ 2.04 (s, 3H), 2.33 (s, 3H), 2.81 (t,2H), 3.28 (m, 2H), 6.19 (bs, 1H), 7.03 (bt, 1H), 7.07 (d, 1H), 7.22 (m,1H), 8.11 (d, 1H), 8.88 (bs, 1H)

[0551] Found C, 65.18%, H, 7.27%, N, 12.70%; C₁₂H₁₆N₂O₂ requires C,65.43%, H, 7.32%. N, 12.72%

Preparation 39: N-[2-(2-Acetylamino-ethyl)-4-chloro-phenyl]-acetamide

[0552]

[0553] A solution of chlorine in glacial acetic acid (1.22M, 29 ml) wasadded dropwise to a solution of the acetamide of preparation 38 (7.78 g,35 mmol) in glacial acetic acid (70 ml) and stirred at room temperaturefor 2 hours. The glacial acetic acid was removed under reduced pressure.The resulting solid was triturated with a mixture of ethyl acetate andpropan-2-ol (7:3, 20 ml) to give the title compound (4.83 g) as a paleyellow solid after filtration.

[0554] ESI MS m/z 277 [M+Na]⁺

[0555]¹H NMR (400 MHz, CDCl₃): δ 2.03 (s, 3H), 2.33 (s, 3H), 2.79 (m,2H), 3.22 (m, 2H), 6.28 (bs, 1H), 7.05 (s, 1H), 7.20 (dd, 1H), 8.14 (d,1H); 9.09 (bs, 1H)

Preparation 40: 2-(2-Amino-ethyl)-4-chloro-phenylamine dihydrochloride

[0556]

[0557] The compound from preparation 39 (4.83 g, 19 mmol) was suspendedin 2 molar aqueous hydrochloric acid (50 ml) and heated to 100° C. for18 hours. Evaporation under reduced pressure gave a red solid which wastriturated with propan-2-ol (15 ml) to give the title compound as a palepink solid (3.5 g) after filtration.

[0558] ESI MS m/z 171 [M+H]⁺

[0559]¹H NMR (400 MHz, DMSO-d₆): δ 3.00 (t, 2H), 3.12 (m, 2H), 7.38 (dd,1H), 7.40 (d, 1H), 7.46 (d, 1H), 8.15 (bs, 3H)

[0560] Found C, 39.29%, H, 5.45%, N, 11.46%; C₈H₁₁N₂.2HCl requires C,39.45%, H, 5.38%, N, 11.50%

Preparation 41:4-Chloro-2-(2-{[5-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[1,3,4]oxadiazol-2-ylmethyl]-amino}-ethyl)-phenylamine

[0561]

[0562] A solution of the amine of preparation 40 (3.5 g, 14.4 mmol) intetrahydrofuran (50 ml) was added to a solution of the oxadiazole ofpreparation 5 (4.0 g, 14.4 mmol) and triethylamine (7.0 ml, 50 mmol) intetrahydrofuran (50 ml) and heated to 50° C. for 4 hours. The reactionmixture was evaporated under reduced pressure and the residue purifiedby chromatography on silica gel using ethyl acetate as eluant followedby methanol and ammonium hydroxide in dichloromethane (5:0.5:95) to givethe title compound as a brown oil (1.35 g).

[0563] APCl MS m/z 413 [M+H]⁺

[0564]¹H NMR (400 MHz, CDCl₃): δ 1.92 (dq, 2H), 2.15 (bdd, 2H), 2.68 (t,2H), 2.93 (t, 2H), 3.07 (dt, 2H), 3.14 (m, 1H), 4.01 (s, 2H), 4.31 (btd,2H), 6.57 (d, 1H), 6.62 (dd, 1H), 6.70 (d, 1H), 6.95-7.02 (m, 2H), 7.27(t, 1H), 8.19 (d, 1H)

Preparation 42: Morpholine-2,4-dicarboxylic acid 4-tert-butyl ester2-ethyl ester

[0565]

[0566] A mixture of 4-phenylmethyl-2-morpholinecarboxylic acid ethylester (J. Med. Chem. 1993, 36(6), 683-9), (8.4 g, 32.4 mmol),di-tert-butyl dicarbonate (8.47 g, 38.9 mmol),1-methyl-1,4-cyclohexadiene (12.37 ml, 110 mmol) and 10% palladium oncharcoal (900 mg) in ethanol (330 ml) was heated to 88° C. for 22 hours.TLC analysis showed starting material remaining, so the reaction wascooled, and additional 1-methyl-1,4-cyclohexadiene (2.37 ml, 21 mmol)and 10% palladium on charcoal (900 mg) were added, and the reactionmixture heated for a further 12 hours at 88° C. The cooled mixture wasfiltered through Arbocel® and the filtrate evaporated under reducedpressure. The residual brown oil was purified by column chromatographyon silica gel using an elution gradient of dichloromethane:methanol(100:0 to 95:5) to give the title compound as a pale yellow oil, 5.97 g.

[0567]¹H NMR (400 MHz, CDCl₃): δ 1.30 (t, 3H), 1.43 (s, 9H), 3.10 (m,2H), 3.50-3.70 (m, 2H), 4.01 (m, 1H), 4.25 (q, 2H).

Preparation 43: Morpholine-2,4-dicarboxylic acid 4-tert-butyl ester

[0568]

[0569] Lithium hydroxide (28 ml, 1M in water, 28 mmol) was added to asolution of the ester from preparation 42 (2.85 g, 11 mmol) intetrahydrofuran (30 ml) and the reaction stirred at room temperature for19 hours. The mixture was acidified to pH 3 using 2M hydrochloric acid,and then extracted with dichloromethane (2×70 ml). The combined organicextracts were dried over magnesium sulphate and evaporated under reducedpressure to give the title compound as a yellow solid, 2.36 g.

[0570]¹H NMR (400 MHz, CDCl₃): δ 1.47 (s, 9H), 3.03-3.11 (m, 3H), 3.60(m, 1H), 3.77-3.86 (m, 1H), 4.02 (m, 1H), 4.15-4.23 (m, 1H).

Preparation 44: 6-Methylene-[1,4]oxazepane-4-carboxylic acid tert-butylester

[0571]

[0572] Sodium hydride (992.6 mg, 60% in mineral oil, 24.8 mmol) wasadded portionwise to a solution of (2-hydroxy-ethyl)-carbamic acidtert-butyl ester (2 g, 12.4 mmol) in 1-methyl-2-pyrrolidinone (20 ml) at−2° C., in order to maintain the temperature below 5° C. The mixture wasthen stirred for 30 minutes, cooled to −5° C., and a solution of3-chloro-2-chloromethyl-1-propene (1.44 ml, 12.4 mmol) in1-methyl-2-pyrrolidinone (10 ml) added dropwise in order to maintain thetemperature below 3° C. Once addition was complete, the reaction mixturewas allowed to warm to room temperature and stirred for a further 18hours. The reaction mixture was diluted with water and extracted withether (2×50 ml). The combined organic extracts were dried over magnesiumsulphate and evaporated under reduced pressure. The residual oil waspurified by column chromatography on silica gel using ethylacetate:pentane (10:90) to give the title compound as a clear oil, 713mg.

[0573]¹H NMR (400 MHz, CDCl₃): δ 1.46 (s, 9H), 3.51 (d, 2H), 3.72 (d,2H), 4.00-4.20 (m, 4H), 4.95 (s, 1H), 5.04 (s, 1H).

[0574] APCl m/z 236 [MNa]⁺

Preparation 45: 6-Oxo-[1,4]oxazepane-4-carboxylic acid tert-butyl ester

[0575]

[0576] Sodium periodate (1.0 g, 4.69 mmol), followed by osmium tetroxide(0.15 ml, 2.5wt % solution in tert-butanol, 0.014 mmol), were added to asuspension of the alkene from preparation 44 (500 mg, 2.34 mmol) indioxan (10 ml) and water (10 ml) and the reaction stirred at roomtemperature for 48 hours. The reaction was diluted with water (50 ml),brine added, and the mixture extracted with ethyl acetate. The combinedorganic extracts were dried over magnesium sulphate and evaporated underreduced pressure to afford the title compound as a brown oil, 567 mg.

[0577]¹H NMR (400 MHz, CDCl₃): δ 1.47 (s, 9H), 3.68 (m, 2H), 3.91 (br m,2H), 4.06 (br m, 2H), 4.11 (s, 2H).

[0578] APCl m/z 233 [M+NH₄]⁺

Preparation 46: 2-(2-Methylamino-ethyl)-phenylamine

[0579]

[0580] A mixture of N-methyl-N-(2-(2-nitrophenyl)ethyl)amine (WO9803473, pg 100) (3 g, 16.65 mmol) and Raney® nickel (500 mg) in ethanol(50 ml) was hydrogenated at 60 psi and room temperature for 2 hours. Themixture was filtered through Celite® and the filtrate evaporated underreduced pressure to give the title compound as an oil.

[0581] APCl MS m/z 152 [MH]⁺

Preparation 47: 2-(1-Methylamino-ethyl)-phenylamine

[0582]

[0583] Acetic acid (10 drops) was added to a solution of methylamine (10g) in dichloromethane (150 ml) cooled to 5° C., followed byo-aminoacetophenone (3.5 g, 25.9 mmol), and the solution stirred for 10minutes. Sodium triacetoxyborohydride (1.5 g, 38.8 mmol) was added andthe reaction stirred at room temperature for 72 hours. The reaction wasdiluted with water, the layers separated, and the organic solutionevaporated under reduced pressure to give the title compound as a yellowoil.

[0584]¹H NMR (400 MHz, CDCl₃): δ 1.44 (s, 3H), 2.36 (s, 3H), 4.77-5.08(br s, 1H), 6.56-6.78 (m, 2H), 7.02 (m, 2H).

Preparation 48: N-{2-[2-(Acetyl-methyl-amino)-ethyl]-phenyl}-acetamide

[0585]

[0586] 4-Methylmorpholine (4.45 g, 44 mmol) and acetic anhydride (4.49g, 44 mmol) were added to an ice-cooled solution of the amine frompreparation 46 (2.2 g, 14.67 mmol) in dichloromethane (50 ml).4-Pyrrolidinopyridine (100 mg, 0.7 mmol) was then added and the reactionmixture stirred at room temperature for 2 hours. The reaction mixturewas then washed with dilute hydrochloric acid (2×), sodium carbonatesolution (2×), and brine (2×). It was dried over magnesium sulphate andevaporated under reduced pressure to afford the title compound as anoil.

[0587]¹H NMR (400 MHz, CDCl₃): δ 2.16 (s, 3H), 2.36 (s, 3H), 2.80 (m,2H), 3.14 (s, 3H), 3.36 (m, 2H), 7.01 (m, 1H), 7.18 (m, 1H), 7.22 (m,1H), 8.22 (d, 1H), 9.22 (s, 1H).

[0588] APCl m/z 235 [MH]⁺

Preparation 49: N-{2-[1-(Acetyl-methyl-amino)-ethyl]-phenyl}-acetamide

[0589]

[0590] The title compound Was obtained as an oil, from the amine frompreparation 47 and acetic anhydride, following a similar procedure tothat described in preparation 48, except that no 4-pyrrolidinopyridinewas added.

[0591]¹H NMR (400 MHz, CDCl₃): ι 1.55 (d, 3H), 2.16 (s, 3H), 2.20 (s,3H), 2.78 (s, 3H), 6.02 (q, 1H), 7.09 (m, 2H), 7.36 (m, 2H), 8.25 (d,1H), 9.40 (br s, 1H).

[0592] APCl MS m/z 257 [MNa]⁺

Preparation 50:N-{2-[2-(Acetyl-methyl-amino)-ethyl]-4-chloro-phenyl}-acetamide

[0593]

[0594] Chlorine (7.3 g) was bubbled into acetic acid (102 g). A portionof this solution (15 g) was added to an ice-cooled solution of thecompound from preparation 48 (3.3 g, 14.1 mmol) in acetic acid (50 ml),and the reaction stirred at room temperature for 20 hours. The mixturewas concentrated under reduced pressure, and the residue dissolved inethyl acetate. This solution was washed with saturated sodium carbonatesolution and brine. It was then dried over magnesium sulphate andevaporated under reduced pressure, to afford the title compound as abrown solid, 2.7 g.

[0595]¹H NMR (400 MHz, CDCl₃): δ 2.16 (s, 3H), 2.30 (s, 3H), 2.78 (m,2H), 3.12 (s, 3H), 3.30 (m, 20 2H), 7.05 (s, 1H), 7.19 (d, 1H), 8.20 (d,1H), 9.38 (s, 1H).

[0596] APCl MS m/z 291 [MNa]⁺

Preparation 51:N-{2-[1-(Acetyl-methyl-amino)-ethyl]-4-chloro-phenyl}-acetamide

[0597]

[0598] Chlorine (1.88 g) was bubbled into a solution of the compoundfrom preparation 49 (6.4 g, 26.6 mmol) in acetic acid (30 ml) and thereaction stirred at room temperature for 24 hours. The mixture wasconcentrated under reduced pressure and the residue suspended in ethylacetate. The solution was then washed with sodium bicarbonate solutionand brine, before being dried over magnesium sulphate and evaporatedunder reduced pressure. The product was recrystallised from isopropylether and methanol to give the title compound, 3.5 g.

[0599]¹H NMR (400 MHz, CDCl₃): δ 1.60 (d, 3H), 2.16 (s, 3H), 2.20 (s,3H), 2.79 (s, 3H), 6.00 (q, 1H), 7.24 (m, 1H), 8.25 (d, 1H), 9.39 (s,1H).

[0600] APCl MS m/z 291 [MH]⁺

Preparation 52: 4-Chloro-2-(2-methylamino-ethyl)-phenylamine

[0601]

[0602] A solution of the compound from preparation 50 (2.6 g, 9.68 mmol)in 2N hydrochloric acid (100 ml) was stirred at 80° C. for 1 hour, and afurther 72 hours at room temperature. TLC analysis showed startingmaterial remaining, so additional 12N hydrochloric acid (50 ml) wasadded and the reaction stirred at 90° C. for a further 3 hours. Thecooled mixture was basified using aqueous 0.88 ammonia, and thenextracted with ethyl acetate (3×). The combined organic extracts werewashed with formaldehyde solution (3×) and brine (2×), before beingdried over magnesium sulphate and evaporated under reduced pressure togive the title compound as an oil, 1.29 g.

[0603]¹H NMR (400 MHz, CDCl₃): δ 2.42 (s, 3H), 2.65 (t, 2H), 2.83 (t,2H), 6.59 (d, 1H), 6.99 (m, 2H).

Preparation 53: 4-Chloro-2-(1-methylamino-ethyl)-phenylamine

[0604]

[0605] A solution of the compound from preparation 49 (3.40 g, 12.65mmol) in 12N hydrochloric acid (150 ml) was stirred at 100° C. for 24hours. The cooled solution was treated carefully with aqueous 0.88ammonia solution, and extracted with dichloromethane (3×). The combinedorganic extracts were dried over magnesium sulphate and evaporated underreduced pressure to give an oil, 2.24 g.

[0606]¹H NMR (400 MHz, CDCl₃): δ 1.42 (d, 3H), 2.38 (s, 3H), 3.76 (q,1H), 6.50 (d, 1H), 6.99 (m, 2H).

[0607] APCl MZ m/z 185 [MH]⁺

Preparation 54: 2-(5-Chloro-2-nitrophenoxy)-ethanol

[0608]

[0609] Sodium hydride (125 mg, 60% dispersion in mineral oil, 3.13 mmol)was added to a mixture of 4-chloro-2-fluoronitrobenzene (500 mg, 2.85mmol) and ethylene glycol (0.18 ml, 3.13 mmol) in1-methyl-2-pyrrolidinone (5 ml) and the reaction stirred at 80° C. for18 hours. TLC analysis showed starting material remaining, so additionalsodium hydride (114 mg, 60% dispersion in mineral oil, 2.85 mmol) andethylene glycol (0.82 ml, 14.25 mmol) were added and the reactionstirred at 110° C. for a further 18 hours. The cooled mixture waspartitioned between water and dichloromethane, and the layers separated.The organic phase was dried over magnesium sulphate and evaporated underreduced pressure. The residue was purified by column chromatography onsilica gel using ethyl acetate:pentane (50:50) as eluant to afford thetitle compound as a solid, 290 mg.

[0610]¹H NMR (400 MHz, CDCl₃): δ 4.00 (t, 2H), 4.22 (t, 2H), 7.04 (d,1H), 7.10 (s, 1H), 7.85 (d, 1H).

Preparation 55: 3-[(5-Chloro-2-nitro-benzyl)-amino]-propionic acidmethyl ester

[0611]

[0612] A mixture of 4 Å molecular sieve powder (16.9 g) and lithiumhydroxide monohydrate (1.80 g, 43 mmol) in N,N-dimethylformamide (100ml) was stirred at room temperature for 20 minutes. β-Alanine methylester hydrochloride (5.0 g, 35.8 mmol) was added and the mixture stirredfor a further 45 minutes. 2-(Bromomethyl)-4-chloro-1-nitrobenzene (J.Het. Chem. 1972; 9(1), 119-22) (8.98 g, 35.8 mmol) was added and thereaction stirred at room temperature for 16 hours. The mixture wasfiltered, the filtrate diluted with ethyl acetate (150 ml), then washedwith brine (3×150 ml) and extracted with 2N hydrochloric acid (2×75 ml).The combined acidic extracts were basified using sodium carbonate, thenextracted with ethyl acetate. The combined organic extracts were driedover magnesium sulphate and evaporated under reduced pressure to affordthe title compound, 1.29 g.

[0613]¹H NMR (400 MHz, CDCl₃): δ 2.56 (t, 2H), 2.90 (t, 2H), 3.69 (s,3H), 4.05 (s, 2H), 7.38 (dd, 1H), 7.72 (d, 1H), 7.94 (d, 1H).

[0614] APCl MS m/z 272 [M−H]⁻

Preparation 56: 3-[(5-Chloro-2-nitro-benzyl)-methyl-amino]-propionicacid methyl ester

[0615]

[0616] Formaldehyde (37% aq solution, 1.2 g, 26 mmol), followed bysodium triacetoxyborohydride (7.7 g, 36.4 mmol) and formic acid (30% aq,3.1 g, 104 mmol), were added to a solution of the amine from preparation55 (7.1 g, 26 mmol) in dichloromethane (70 ml), and the reaction stirredat room temperature for 18 hours. The mixture was concentrated underreduced pressure, the residue diluted with ethyl acetate, and thesolution washed with 1N sodium hydroxide and brine. The solution wasconcentrated under reduced pressure and the crude product purified bycolumn chromatography on silica gel using an elution gradient ofpentane:ethyl acetate (100:0 to 95:5) to give the title compound, 6 g.

[0617]¹H NMR (400 MHz, CDCl₃): δ 2.20 (s, 3H), 2.44 (t, 2H), 2.72 (t,2H), 3.64 (s, 3H), 3.78 (s, H), 7.35 (dd, 1H), 7.63 (s, 1H), 7.80 (d,1H).

Preparation 57: 2-(2-Amino-5-chloro-phenoxy)-ethanol

[0618]

[0619] A mixture of the compound from preparation 56 (280 mg, 1.29 mmol)and platinum oxide (80 mg) in ethanol (25 ml) was hydrogenated at roomtemperature and 60 psi for 5 hours. The mixture was filtered, washingthrough with further ethanol, and the filtrate evaporated under reducedpressure. The crude product was purified by column chromatography onsilica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) toafford the title compound as an off-white solid, 195 mg.

[0620]¹H NMR (400 MHz, CDCl₃): δ 3.98 (t, 2H), 4.16 (t, 2H), 6.75 (d,1H), 6.82 (m, 2H).

[0621] APCl MS m/z 188 [MH]⁺

Preparation 58: 3-[(2-Amino-5-chloro-benzyl)-methyl-amino]-propionicacid methyl ester

[0622]

[0623] A mixture of the compound from preparation 56 (6.01 g, 22.0mmol), and platinum oxide (500 mg) in ethanol (100 ml) was hydrogenatedat 60 psi and room temperature for 1 hour. The mixture was filteredthrough Celite®, and the filtrate evaporated under reduced pressure. Thecrude product was purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (90:10:1) to afford the titlecompound.

[0624]¹H NMR (400 MHz, CDCl₃): δ 2.16 (s, 3H), 2.50 (t, 2H), 2.72 (t,2H), 3.44 (s, 2H), 3.63 (s, 3H), 4.62 (br s, 2H), 6.56 (d, 1H), 6.98 (s,1H), 7.01 (dd, 1H).

Preparation 59: 3-[(2-Amino-5-chloro-benzyl)-methyl-amino]-propionicacid dihydrochloride

[0625]

[0626] A mixture of the ester from preparation 58 (1.1 g, 4.3 mmol) intetrahydrofuran (10 ml), water (1.4 ml) and hydrochloric acid in dioxan(4M, 10 ml) was stirred at room temperature for 2 hours, followed by anadditional 8 hours at 90° C. The cooled solution was concentrated underreduced pressure and the residue azeotroped with ethyl acetate andtoluene to afford the title compound.

[0627]¹H NMR (400 MHz, DMSOd₆): δ 2.62 (s, 3H), 2.81 (t, 2H), 3.30 (t,2H), 4.22 (s, 2H), 6.78 (m, 1H), 7.18 (d, 1H), 7.39 (s, 1H).

[0628] APCl MS m/z 243 [MH]⁺

Preparation 60:Methyl-[5-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[1,3,4]oxadiazol-2-ylmethyl]-amine

[0629]

[0630] Methylamine (2.23 ml, 33% solution in ethanol, 17.9 mmol) wasadded to a solution of the chloride from preparation 5 (1 g, 3.59 mmol)in tetrahydrofuran (20 ml), and the solution stirred at room temperaturefor 18 hours. Additional methylamine (10 ml, 33% solution in ethanol)was added and the reaction stirred for a further 72 hours. The reactionwas evaporated under reduced pressure, the solid triturated with ethylacetate and the precipitate removed by filtration. The filtrate wasconcentrated under reduced pressure and the residue azeotroped withdichloromethane to afford the title compound as a crystalline solid.

[0631]¹H NMR (400 MHz, CDCl₃): δ 1.98 (m, 2H), 2.17 (brd, 2H), 2.48 (s,3H), 3.18 (t, 2H), 3.35 (m, 1H), 3.95 (s, 2H), 4.58 (brd, 2H), 6.62 (dd,1H), 6.68 (d, 1H), 7.46 (dd, 1H), 8.18 (d, 1H).

[0632] APCl m/z 274 [MH]⁺

Preparation 61:4-Chloro-2-{2-[5-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[1,3,4]oxadiazol-2-ylmethoxy]-ethoxy}-phenylamine

[0633]

[0634] Sodium hydride (60% dispersion in mineral oil, 45 mg, 1.1 mmol)was added to an ice-cooled solution of the alcohol from preparation 57(190 mg, 1 mmol) in tetrahydrofuran (10 ml), and the solution stirredfor 30 minutes. A solution of the chloride from preparation 5 (310 mg,1.1 mmol) in tetrahydrofuran (6 ml) was added and the reaction stirredat room temperature for 18 hours. The reaction was quenched by theaddition of water (1 ml) and the mixture was then partitioned betweendichloromethane and saturated aqueous sodium bicarbonate solution. Thelayers were separated, the organic phase dried over magnesium sulphateand evaporated under reduced pressure. The residue was purified bycolumn chromatography on silica gel using an elution gradient of ethylacetate:methanol (96:4 to 95:5) to afford the title compound as a paleorange oil, 280 mg.

[0635]¹H NMR (400 MHz, CDCl₃): δ 1.99 (m, 2H), 2.20 (m, 2H), 3.18 (m,3H), 2.96 (m, 2H), 4.18 (m, 2H), 4.30 (m, 2H), 4.80 (s, 2H), 6.60-6.80(m, 5H), 7.55 (m, 1H), 8.20 (m, 1H).

[0636] APCl MS m/z 452 [MNa]⁺

Preparation 62:2-Amino-5-chloro-N-methyl-N-[5-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[1,3,4]oxadiazol-2-ylmethyl]-benzamide

[0637]

[0638] 5-Chloroanthranallic acid (314 mg, 1.83 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (350 mg,1.83 mmol) and N-methyl morpholine (0.4 ml, 3.64 mmol) were added to asolution of the amine from preparation 60 (500 mg, 1.83 mmol) indichloromethane (20 ml) and the reaction stirred at room temperature for3 hours. The reaction mixture was washed with 10% citric acid solution,saturated sodium bicarbonate solution, and brine, then dried overmagnesium sulphate and evaporated under reduced pressure. The combinedaqueous phases were extracted with dichloromethane (2×25 ml), and thecombined dichloromethane extracts evaporated under reduced pressure. Thecombined crude products were purified by column chromatography on silicagel using ethyl acetate as eluant, and the product azeotroped withdichloromethane and ether to afford the title compound as a white solid,278 mg.

[0639]¹H NMR (400 MHz, CDCl₃): δ 1.92 (m, 2H), 2.16 (d, 2H), 3.02-3.22(m, 6H), 4.32 (d, 2H), 4.85 (br s, 2H), 6.63 (m, 2H), 6.70 (d, 1H), 7.14(m, 2H), 7.50 (dd, 1H), 8.20 (d, 1H).

[0640] APCl MS m/z 427 [MH]⁺

Preparation 63:4-Chloro-2-(2-{methyl-[5-(1-pyrimidin-2-yl-piperidin-4-yl)-[1,3,4]oxadiazol-2-ylmethyl]-amino}-ethyl)-phenylamine

[0641]

[0642] A mixture of the amine from preparation 52 (1.1 g, 5.96 mmol),the chloride from preparation 6 (1.51 g, 5.42 mmol), N-methylmorpholine(0.60 g, 5.96 mmol) and sodium iodide (400 mg, 2.66 mmol) intetrahydrofuran (50 ml) was stirred at 50° C. for 18 hours. The reactionwas concentrated under reduced pressure and the residue was dissolved inethyl acetate. The solution washed with water (3×) and brine, then driedover magnesium sulphate and evaporated under reduced pressure, to givethe title compound as a yellow oil, 1.77 g.

[0643] APCl MS m/z 428 [MH]⁺

Preparation 64:4-Chloro-2-(1-{[4-(4-chloro-phenyl)-5-(1-pyrimidin-2-yl-piperidin-4-[1,2,4]triazol-3-ylmethyl]-methyl-amino}-ethyl)-phenylamine

[0644]

[0645] A mixture of the chloride from preparation 6 (1.37 g, 4.92 mmol),the amine from preparation 53 (1.0 g, 5.41 mmol), and potassiumcarbonate (0.75 g, 5.41 mmol) in tetrahydrofuran (50 ml) was stirred atroom temperature for 18 hours. Sodium iodide (40 mg, 2.67 mmol) wasadded and the reaction stirred for a further 24 hours. The reaction wasconcentrated under reduced pressure, the residue dissolved in ethylacetate and the solution washed with brine. The solution was dried overmagnesium sulphate and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel usingdichloromethane:methanol (99:1) to give the title compound as an oil,1.30 g.

[0646]¹H NMR (400 MHz, CDCl₃): δ 1.45 (d, 3H), 1.86 (m, 2H), 2.18 (m,2H), 2.35 (s, 3H), 3.20 (m, 3H), 3.78 (m, 2H), 3.88 (d, 1H), 4.74 (m,2H), 6.50 (dd, 1H), 6.58 (d, 1H), 7.00 (m, 2H), 8.32 (s, 2H).

[0647] APCl MS m/z 428 [MH]⁺

Preparation 65:3-[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carbonyl]-pyrrolidine-1-carboxylicacid tert-butyl ester

[0648]

[0649] 1-Hydroxybenzotriazole hydrate (426 mg, 3.16 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (658 mg,3.42 mmol), triethylamine (0.91 ml, 6.58 mmol) and1-tert-butyl-1,3-pyrrolidinedicarboxylate (J. Med. Chem. 44; 1; 2001;94-1004) (900 mg, 3.95 mmol) were added to a suspension of the aminefrom example 4 (1 g, 2.63 mmol) in dichloromethane (20 ml), and thereaction stirred at room temperature for 3 hours. TLC analysis showedstarting material remaining, so additional 1-hydroxybenzotriazolehydrate (355 mg, 2.63 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (506 mg,2.63 mmol) and 1-tert-butyl-1,3-pyrrolidinedicarboxylate (600 mg, 2.63mmol) were added and the reaction stirred for a further 18 hours. Themixture was partitioned between 2N sodium hydroxide solution anddichloromethane and the layers separated. The organic solution wasevaporated under reduced pressure and the,residue purified by columnchromatography on silica gel using dichloromethane:methanol (95:5) aseluant to afford the title compound as an off-white foam, 690 mg.

[0650]¹H NMR (400 MHz, CDCl₃): δ 1.41 (s, 9H), 1.68-2.30 (m, 6H),2.81-3.18 (m, 3H), 3.20-3.81 (m, 5H), 3.83-5.36 (m, 6H), 6.60 (dd, 1H),6.66 (d, 1H), 7.38-7.62 (m, 4H), 8.18 (m, 1H).

[0651] APCl MS m/z 578 [MH]⁺

Preparations 66 to 72:

[0652] The following preparations of general formula:

[0653] were prepared from the amine from example 4 and the appropriateacid, following a similar procedure to that described in preparation 65.Yield (%)/ Prep No R¹ Form Data 66

42 ¹H NMR (400MHz, CDCl₃): δ1.06-1.58 (m, 11H), 1.78-2.40 (m, 6H),2.80-3.20 (m, 3H), 3.40-3.77 (m, 3H), 4.19-4.62 (m, 4H), 5.02-5.60 (m,2H), 6.58-6.72 (m, 2H), 7.37-7.66 (m, 4H), 8.18 (m, 1H). APCI MS m/z 577[M − H]⁻ 67

79 ¹H NMR (400MHz, CDCl₃): δ1.06-1.58 (m, 11H), 1.78-2.40 (m, 6H),2.80-3.20 (m, 3H), 3.40-3.77 (m, 3H), 4.19-4.62 (m, 4H), 5.02-5.60 (m,2H), 6.58-6.72 (m, 2H), 7.37-7.66 (m, 4H), 8.18 (m, 1H). APCI MS m/z 577[M − H]⁻ 68

85 APCI MS m/z 591 [M − H]⁻ 69

58 white foam APCI MS m/z 592 [MH]⁺ 70

58 white foam APCI MS m/z 592 [MH]⁺ 71^(a)

55 off-white foam APCI MS m/z 594 [MH]⁺ 72

69 APCI MS m/z 616 [MNa]⁺

Preparation 73:3-[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-52,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-azetidine-1-carboxylic acidtert-butyl ester

[0654]

[0655] 3-Oxo-azetidine-1-carboxylic acid tert-butyl ester (JP2002/255932, pg 6) (562 mg, 3.16 mmol) and sodium triacetoxyborohydride(1.12 g, 5.26 mmol) were added to a suspension of the amine from example4 (1 g, 2.63 mmol) in dichloromethane (50 ml), and the reaction stirredat room temperature for 72 hours. The mixture was partitioned between 2Nsodium hydroxide and dichloromethane, the layers separated, and theorganic phase evaporated under reduced pressure. The residual yellow oilwas purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant to afford thetitle compound as a white foam.

[0656]¹H NMR (400 MHz, CDCl₃): δ 1.42 (s, 9H), 1.60-2.46 (m, 4H),2.90-3.00 (m, 2H), 3.12 (m, 1H), 3.50 (m, 2H), 3.79-3.90 (m, 3H),3.99-4.60 (m, 6H), 6.60 (m, 1H), 6.60 (d, 1H), 7.28 (d, 1H), 7.42-7.56(m, 2H), 7.58 (dd, 1H), 8.18 (m, 1H).

[0657] APCl MS m/z 558 [MNa]⁺

Preparation 74:3-[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester

[0658]

[0659] The title compound was obtained as an off-white solid in 53%yield from the amine from example 4 and 3-oxo-pyrrolidine-1-carboxylicacid tert-butyl ester, following a similar procedure to that describedin preparation 73, except that acetic acid (3 drops) was also added tothe reaction.

[0660]¹H NMR (400 MHz, CDCl₃): δ 1.44 (s, 9H), 1.50-1.70 (m, 2H),1.75-2.55 (m, 5H), 2.80-3.90 (m, 11H), 4.20-4.45 (m, 2H), 6.60 (dd, 1H),6.66 (d, 1H), 7.35 (d, 1H), 7.41-7.57 (m, 3H), 8.18 (d, 1H).

[0661] APCl MS m/z 572 [MNa]⁺

Preparation 75:4-[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-piperidine-1-carboxylicacid tert-butyl ester

[0662]

[0663] tert-Butyl-4-oxo-piperidinecarboxylate (628 mg, 3.16 mmol) andsodium triacetoxyborohydride (1.12 g, 5.26 mmol) were added to asuspension of the amine from example 4 (1 g, 2.63 mmol) indichloromethane (50 ml), and the reaction was stirred at roomtemperature for 72 hours. TLC analysis showed starting materialremaining, so additional tert-butyl-4-oxo-piperidinecarboxylate (628 mg,3.16 mmol) and sodium riacetoxyborohydride (1.12 g, 5.26 mmol) wereadded, and the reaction stirred for a further 5 hours. The mixture waspartitioned between 2N sodium hydroxide (100 ml) and dichloromethane(100 ml), and the layers were separated. The organic phase was washedwith brine (100 ml), dried over magnesium sulphate and evaporated underreduced pressure to afford the title compound as a colourless gum.

[0664]¹H NMR (400 MHz, CDCl₃): δ 1.42 (s, 9H), 1.72-2.20 (m, 8H), 2.40(m, 2H), 2.61-2.78 (m, 1H), 2.92-3.20 (m, 2H), 3.40-3.60 (m, 1H), 3.70(m, 2H), 3.82 (m, 2H), 4.04-4.19 (m, 2H), 4.34 (m, 2H), 6.60 (m, 1H),6.66 (d, 1H), 7.32 (d, 1H), 7.42-56 (m, 3H), 8.18 (m, 1H).

Preparation 76:6-[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-[1,4]oxazepane-4-carboxylicacid

[0665]

[0666] A solution of the ketone from preparation 45 (286 mg, 1.33 mmol)in dichloromethane (5 ml) followed by sodium triacetoxyborohydride(281.5 mg, 1.33 mmol) was added to a suspension of the amine fromexample 4 (500 mg, 1.31 mmol) in dichloromethane (20 ml), and thereaction stirred at room temperature for 18 hours. TLC analysis showedstarting material remaining, so additional ketone (250 mg, 1.16 mmol)was added, and the reaction stirred for a further 70 hours. Saturatedsodium bicarbonate solution (15 ml) was added and the mixture stirred atroom temperature for 30 minutes. The layers were separated and theorganic phase was washed with brine, dried over magnesium sulphate andevaporated under reduced pressure. The residual brown oil was purifiedby column chromatography on silica gel using dichloromethane:methanol(95:5) as eluant to afford the title compound, 189 mg.

[0667] APCl MS m/z 580 [MH]⁺

Preparation 77:1-[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-2-dimethylamino-ethanone

[0668]

[0669] 1-Hydroxybenzotriazole hydrate (107 mg, 0.79 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (184 mg,0.86 mmol), triethylamine (0.23 ml, 1.65 mmol) and N,N-dimethyl glycine(71.2 mg, 0.69 mmol) were added to a suspension of the amine fromexample 4 (250 mg, 0.66 mmol) in dichloromethane (10 ml) and thereaction stirred at room temperature for 18 hours. The reaction waspartitioned between 2N sodium hydroxide solution (10 ml) anddichloromethane (10 ml), the layers separated, and the aqueous phaseextracted with further dichloromethane (10 ml). The combined organicsolutions were washed with brine (20 ml), dried over magnesium sulphateand evaporated under reduced pressure. The residual gum was purified bycolumn chromatography on silica gel using dichloromethane:methanol:0.88ammonia (95:5:0.5) to give the title compound as a white foam, 220 mg.

[0670]¹H NMR (400 MHz, CDCl₃): δ 1.58-1.88 (m, 4H), 2.20-2.40 (2xs, 6H),2.60-4.60 (m, 9H), 5.28-5.60 (m, 2H), 6.60 (m, 1H), 6.66 (d, 1H), 7.40(dd, 1H), 7.46 (m, 1H), 7.57 (m, 1H), 7.60 (d, 1H), 8.18 (m, 1H).

[0671] APCl MS m/z 466 [MH]⁺

Preparation 78:8-Chloro-5-methyl-3,4,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-2-one

[0672]

[0673] A mixture of the compound from preparation 59 (1.35 g, 4.3 mmol),N-methylmorpholine (2.2 ml, 19.3 mmol) and O-benzotriazol-1-yl-N,N,N′;N′-tetramethyluronium hexafluorophosphate (2.3 g, 6 mmol) indichloromethane (100 ml) was stirred at room temperature for 18 hours.The reaction was washed with 1M sodium hydroxide solution (3×), waterand brine, then dried over magnesium sulphate and concentrated underreduced pressure. The residue was triturated with ethyl acetate and theresulting solid filtered off and dried to afford the title compound. Thefiltrate was concentrated under reduced pressure and the residue waspurified by column chromatography on silica gel usingdichloromethane:methanol (100:0 to 95:5) to afford additional titlecompound, 550 mg as a white solid (in total).

[0674]¹H NMR (400 MHz, CDCl₃): ι 2.30 (m, 2H), 2.45 (s, 3H), 2.98 (m,2H), 3.60 (s, 2H), 7.04 (d, 1H), 7.25 (d, 1H), 7.38 (s, 1H), 7.78 (br s,1H).

[0675] APCl MS m/z 225 [MH]⁺

Preparation 79:8-Chloro-5-methyl-3,4,5,6-tetrahydro-1H-benzo[b][1,5]diazocine-2-thione

[0676]

[0677] Sodium carbonate (254 mg, 2.4 mmol) was added to a solution ofphosphorous pentasulphide (1.07 g, 2.4 mmol) in tetrahydrofuran (5.5 ml)at 5° C. The solution was cooled to 3° C., and the compound frompreparation 78 (540 mg, 2.4 mmol) was added. Water (83 μl, 4.6 mmol) wasadded dropwise, and the resulting mixture was stirred at roomtemperature for 18 hours. The reaction was diluted with 0.88 ammonia,and extracted with dichloromethane (2×). The combined organic extractswere washed with brine, dried over magnesium sulphate and evaporatedunder reduced pressure. The residue was adsorbed onto silica gel andpurified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1) to afford thetitle compound (0.23 g).

[0678]¹H NMR (400 MHz, CDCl₃): δ 2.42 (s, 3H), 2.78 (m, 2H), 3.12 (m,2H), 3.60 (s, 2H), 7.10 (d, 1H), 7.33 (d, 1H), 7.40 (s, 1H), 9.50 (br s,1H).

[0679] APCl MS m/z 241 [MH]⁺

Preparation 80:8-Chloro-5-methyl-2-methylsulphanyl-3,4,5,6-tetrahydro-benzo[b][1,5]diazocine

[0680]

[0681] Potassium tert-butoxide (0.55 ml, 1M in tetrahydrofuran, 0.55mmol) was added dropwise to a solution of the compound from preparation79 (131 mg, 0.55 mmol) in tetrahydrofuran (2 ml), and the solution thenstirred for 30 minutes. P-Methyl toluene sulphonate (102.4 mg, 0.55mmol) was added and the reaction stirred at room temperature for 3hours. The mixture was concentrated under reduced pressure and theresidue partitioned between dichloromethane and water, and the layersseparated. The organic phase was washed with brine, dried over magnesiumsulphate and concentrated under reduced pressure to give the titlecompound (152 mg).

[0682] APCl MS m/z 255 [MH]⁺

Preparation 81: (2-Amino-5-chloro-benzylamino)-acetic acid tert-butylester

[0683]

[0684] Chloro-acetic acid tert-butyl ester (500 mg, 3.34 mmol) was addedto a solution of the amine of preparation 10 (1.04 g, 6.65 mmol) in THF(20 ml) and the reaction mixture was heated to 65° C. for 20 hours. Themixture was allowed to cool and was filtered. The filtrate wasevaporated under reduced pressure and the resulting gummy residue waspurified by column chromatography on silica gel using ethyl acetate toelute to give the title compound (726 mg) as a white crystalline solid.

[0685]¹H NMR (400 MHz, CD₃OD): δ 1.50 (s, 9H), 3.28 (s, 2H), 3.67 (s,2H), 6.68 (d, 1H), 7.00 (d, 1H), 7.02 (s, 1H).

[0686] APCl MS m/z 271 [MH]⁺, 293 [MNa]⁺

Preparation 82: 7-Chloro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one

[0687]

[0688] To a degassed solution of the ester of preparation 81 (49.2 g,181.7 mmol) in THF (500 ml) was added potassium tert-butoxide (20.38 g,181.6 mmol) and the mixture stirred at room temperature for 2 hours. Asecond addition of potassium tert-butoxide (2.04 g, 18.2 mmol) was madeand stirring continued for 15 minutes before a saturated solution ofammonium chloride was added (150 ml). The resulting mixture wasextracted with ethyl acetate (4 dm³). The organic extracts were dried(MgSO₄) and filtered. The filtrate was evaporated under reduced pressureto give a yellow solid which was triturated twice with pentane (150 ml)and filtered to give the title compound as an off-white crystallinesolid (31.1 g).

[0689]¹H NMR (400 MHz, CD₃OD): δ 3.54 (s, 2H), 3.92 (s, 2H), 7.02 (d,1H), 7.25 (d, 1H), 7.27 (s, 1H).

Preparation 83:7-Chloro-4-methyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one

[0690]

[0691] Formaldehyde (37% w/v aqueous, 5 ml, 60 mmol) was added to asuspension of the amine of preparation 82 (8.4 g, 42.7 mmol) indichloromethane (140 ml) and acetic acid (1 ml). The mixture was stirredat room temperature for 0.25 hours before adding sodiumtriacetoxyborohydride (14 g, 64.1 mmol) portionwise, and it was stirredfor a further 30 minutes. The reaction mixture was partitioned between2N aqueous hydrochloric acid (50 ml) and dichloromethane (200 ml). Theorganic layer was extracted a second time with 2N aqueous hydrochloricacid (50 ml) before being discarded. The combined acid layers were madebasic with 2N causing precipitation of a pale yellow solid, which wasfiltered off. The filtrate was extracted twice with dichloromethane(2×100 ml) and added to a solution of the pale yellow solid filter cakethat had been dissolved in dichloromethane (500 ml). The combineddichloromethane layers were dried (MgSO₄), filtered and the filtrateevaporated under reduced pressure to give a yellow solid. Triturationwith diethyl ether gave the title compound as a pale yellow solid (7.1g).

[0692]¹H NMR (400 MHz, CDCl₃): δ 2.54 (s, 3H), 3.42 (s, 2H), 3.77 (s,2H), 6.94 (d, 1H), 7.24 (m, 2H), 8.58 (s, 1H).

[0693] APCl MS m/z 211 [MH]⁺, 233 [MNa]⁺

Preparation 84:7-Chloro-4-methyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepine-2-thione

[0694]

[0695] Sodium carbonate (1.06 g, 10 mmol) was added to a suspension ofphosphorous pentasulphide (4.45 g, 10 mmol) in tetrahydrofuran (25 ml)at 5° C. The solution was cooled to 3° C., and the compound frompreparation 83 (2.11 g, 10 mmol) was added. Water (1 ml) was addeddropwise, and the resulting mixture was stirred at room temperature for18 hours. The reaction was diluted with 0.88 ammonia (50 ml) andextracted with dichloromethane (2×200 ml). The combined organic extractswere washed with brine, dried over magnesium sulphate and evaporatedunder reduced pressure. The residue was purified by columnchromatography on silica gel using ethyl acetate as eluant, to affordthe title compound as a yellow solid (2.11 g)

[0696]¹H NMR (400 MHz, CDCl₃): δ 2.62 (s, 3H), 3.61 (s, 2H), 3.67 (s,2H), 7.00 (d, 1H), 7.34 (m, 2H), 10.1 (s, 1H).

[0697] APCl MS m/z 227 [MH]⁺

Preparation 85: (5-Chloro-2-nitro-benzylsulfanyl)-acetic acid

[0698]

[0699] Mercapto-acetic acid (1.39 ml, 20 mmol) was dissolved in a 3.3molar aqueous solution of sodium hydroxide (12 ml, 40 mmol) and cooledin an ice bath, before an acetone (50 ml) solution of2-Bromomethyl-4-chloro-1-nitro-benzene (T. J. McCord et al, J. Het.Chem. 1972, 119-122)(5 g, 20 mmol) was added slowly. The resultingsolution was stirred for 20 hours at room temperature before beingdiluted with water (50 ml) and extracted with dichloromethane (25 ml).The aqueous phase was made acidic with acetic acid and extracted withdichloromethane (2×25 ml). The combined organics were washed with brine,dried (MgSO₄), filtered and evaporated to give the title product as anoff-white foam (3.65 g).

[0700]¹H NMR (400 MHz, CDCl₃): δ 3.15 (s, 2H), 4.20 (s, 2H), 7.40 (d,1H), 7.50 (s, 1H), 8.00 (d, 1H), 11.85 (brs, 1H).

[0701] APCl MS m/z 260 [MH]⁺

Preparation 86: 2-Chloro-5,9-dihydro-8-thia-5-aza-benzocyclohepten-6-one

[0702]

[0703] To a solution of the nitro compound of preparation 85 (2.59 g,9,9 mmol) in ethanol (100 ml) was added platinum oxide (1 g). Themixture was hydrogenated at room temperature, under a pressure of 40p.s.i. for 1 hour. The reaction mixture was allowed to cool beforefiltering through a plug of Arbocel®. The filtrate was evaporated andthe residue suspended in xylene (50 ml) before heating to 150° C. for 20hours. The mixture was allowed to cool and purified by columnchromatography on silica gel using dichloromethane to elute, followed byethyl acetate, to afford a buff solid which was triturated with diethylether to afford the title compound as a white solid (850 mg)

[0704]¹H NMR (400 MHz, CDCl₃): δ 3.05 (s, 2H), 3.80 (s, 2H), 7.00 (d,1H), 7.30 (dd, 1H), 7.35 (s, 1H), 7.90 (s, 1H).

[0705] APCl MS m/z 212 [MH]⁺

Preparation 87:2-Chloro-5,9-dihydro-8-thia-5-aza-benzocycloheptene-6-thione

[0706]

[0707] Sodium carbonate (394 mg, 3.7 mmol) was added to a suspension ofphosphorous pentasulphide (1.65 g, 3.7 mmol) in tetrahydrofuran (20 ml)at 5° C. The solution was cooled to 3° C., and the compound frompreparation 86 (750 mg, 3.5 mmol) was added. Water (4 drops) was addeddropwise, and the resulting mixture stirred at room temperature for 18hours. The reaction mixture was diluted with 0.880 ammonia (75 ml), andextracted with dichloromethane (2×35 ml). The combined organic extractswere washed with brine, dried over magnesium sulphate and evaporatedunder reduced pressure to afford the title compound as a white solid(603 mg).

[0708]¹H NMR (400 MHz, CDCl₃): δ 3.55 (s, 2H), 3.85 (s, 2H), 7.00 (dd,1H), 7.35 (m, 2H), 9.20 (br s, 1H).

[0709] APCl MS m/z 230 [MH]⁺

Preparation 88: 2-amino-5-chloro-N-methylbenzamide

[0710]

[0711] To a solution of 5-chloroisatoic anhydride (10.0 g, 51 mmol) intetrahydrofuran (100 ml) at ambient temperature was added a 40% w/waqueous solution of methylamine (19.80 g, 255 mmol) dropwise. Themixture was stirred at an ambient temperature for 1 hour. Ethyl acetate(100 ml) and water (100 ml) were added and the phases separated. Theaqueous layer was back extracted with ethyl acetate (100 ml) and thecombined organics were evaporated under reduced pressure to afford awhite solid, which was recrystallised from toluene (60 ml) to afford thetitle compound as a white solid (8.15 g)

[0712]¹H NMR (400 MHz, CDCl₃): δ 2.86 (s, 3H), 6.71-6.73 (d, 1H),7.11-7.14 (m, 1H), 7.41 (s, 1H)

Preparation 89: (2-amino-5-chlorobenzyl)methylamine

[0713]

[0714] To a suspension of 2-amino-5-chloro-N-methylbenzamide (20.08 g,109 mmol) and sodium borohydride (12.37 g, 327 mmol) in tetrahydrofuran(200 ml) was added boron trifluoride diethyl etherate, dropwise, atT<15° C. The mixture was stirred at an ambient temperature for 1 hourbefore heating to reflux for 6 hours. The reaction mixture was cooled inan ice water bath and a solution of piperazine (75.08 g, 872 mmol) inwater (530 ml) was added dropwise. The mixture was then heated to refluxfor 16 hours. The mixture was cooled to an ambient temperature and ethylacetate (100 ml) was added. The phases were separated and the aqueouslayer back extracted with ethyl acetate (40 ml). The combined organicphases were washed with water (3×80 ml) and evaporated under reducedpressure to afford an orange oil (17.58 g, 103 mmol)). The oil wasdissolved in ethyl acetate (175 ml) and benzenesulfonic acid (16.29 g,103 mmol) and stirred at an ambient temperature for 2 hours. The whiteprecipitate was collected by filtration to afford the benzenesulfonatesalt (24.12 g). The white solid was partitioned between dichloromethane(240 ml) and 2M sodium hydroxide (240 ml) and the phases were separated.The organic phase was evaporated under reduced pressure to afford thetitle compound as a colourless oil (10.78 g)

[0715]¹H NMR (400 MHz, CDCl₃): δ 2.42 (s, 3H), 3.72 (s, 2H), 6.55-6.57(d, 1H), 7.00-7.04 (m, 2H)

Preparation 90:(2-amino-5-chlorobenzyl)methyl{[5-(1-pyridin-2-ylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl]methyl}amine

[0716]

[0717] The oxadiazole of preparation 5b (2.77 g, 9.93 mmol) was heatedat reflux with the amine of preparation 89 (2.53 g, 14.9 mmol) andsodium hydrogen carbonate (0.88 g, 10.43 mmol) in acetonitrile for 5hours. The mixture was cooled and water (20 ml) and dichloromethane (20ml) were added. The phases were separated and the organic phase wasevaporated under reduced pressure to afford the title compound as an oil(4.8 g)

[0718]¹H NMR (400 MHz, CDCl₃): δ 1.91-2.01 (m, 2H), 2.16-2.20 (m, 2H),2.33 (s, 3H), 3.07-3.21 (m, 3H), 3.57 (s, 2H), 3.79 (s, 2H), 4.29-4.33(m, 2H), 6.55-6.57 (d, 1H), 6.62-6.65 (m, 1H), 6.69-6.71 (d, 1H), 6.98(m, 1H), 7.03-7.05 (m, 1H), 7.47-7.51 (m, 1H), 8.19-8.20 (m, 1H)

Preparation 91:8-Chloro-5-methyl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulenedibesylate

[0719]

[0720] To a suspension of8-Chloro-5-methyl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene(25.3 g, 64 mmol) in methanol (250 ml) was added benzenesulfonic acid(20.3 g, 128 mmol). The yellow solution was heated to 60° C. for 1 hourand then allowed to cool to ambient temperature and stirred for 16hours. The mixture was cooled in iced water for 1 hour before filteringunder vacuum to afford a white granular solid which, after being driedat 50° C. under vacuum for 16 hours, afforded the title compound (41.3g).

[0721]¹H NMR (400 MHz, D₂O): δ 1.62-1.82 (m, 2H), 2.04-2.20 (m, 1H),2.31-2.43 (m, 1H), 2.98 (s, 3H), 3.08-3.23 (m, 1H), 3.30-3.43 (m, 1H),3.44-3.54 (m, 1H), 3.84-4.02 (m, 2H), 4.02-4.13 (m, 1H), 4.13-4.27 (m,1H), 4.27-4.40 (m, 1H), 6.81-6.90 (m, 1H), 7.17-7.19 (d, 1H), 7.40-7.54(m, 6H), 7.62-7.73 (m, 5H), 7.73-7.82 (m, 3H), 7.82-7.94 (m, 1H); (FoundC, 55.6; H, 5.0; N, 11.8%. C₃₃H₃₅CIN₆O₆S₂ requires C, 55.7; H, 5.0; N,11.8%).

EXAMPLE 11-(3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[0722]

[0723] Toluene-4-sulfonic acid (100 mg, 0.58 mmol) was added to asolution of the oxadiazole of preparation 13 (2.45 g, 6.8 mmol) andheated to 150° C. for 18 hours. The mixture was cooled and purified bychromatography on silica gel using methanol and ammonium hydroxide indichloromethane (5:0.5:95) as eluant, followed by chromatography onsilica gel using methanol and ammonium hydroxide in ethyl acetate(10:1:90), followed by methanol and ammonium hydroxide indichloromethane (7:1:93) as eluant to give, after trituration with ethylacetate, the title compound (770 mg) as a brown solid.

[0724] APCl MS m/z 347 [MH]⁺

[0725]¹H NMR (400 MHz, CDCl₃): δ 1.80-2.40 (m, 4H), 2.95 (m, 2H), 3.20(m, 1H), 3.73 (s, 2H), 3.88 (s, 2H), 4.33 (m, 2H), 6.57 (m, 1H), 6.68(d, 1H), 7.37 (d, 1H), 7.50 (m, 4H), 8.17 (d, 1H)

EXAMPLE 25-Methyl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[0726]

[0727] Formaldehyde (37% w/v aqueous, 1 ml, 81 mmol) was added to asolution of the amine of example 1 (100 mg, 0.28 mmol) indichloromethane (20 ml). The mixture was stirred at room temperature for0.25 hours before sodium triacetoxyborohydride (500 mg, 2.4 mmol) wasadded. The reaction mixture was stirred for a further 0.25 hours. Thedichloromethane was removed under reduced pressure. The residue waspartitioned between 2N aqueous sodium hydroxide solution (50 ml) andethyl acetate (50 ml). The organic layer was washed with saturated brineand dried over magnesium sulphate before filtering and evaporating thefiltrate under reduced pressure to give the title compound as a paleyellow foam (75 mg)

[0728] APCl MS m/z 361 [MH]⁺, 384 [MNa]⁺

[0729]¹H NMR (400 MHz, CDCl₃): δ 2.08 (m, 4H), 2.52 (s, 3H), 3.00 (m,2H), 3.21 (m, 2H), 3.40 (s, 2H), 3.70 (s, 2H), 4.36 (m, 2H), 6.60 (m,1H), 6.68 (d, 1H), 7.40 (d, 1H), 7.50 (m, 4H), 8.18 (d, 1H)

EXAMPLE 3 1-[1-(3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-ethanone

[0730]

[0731] Acetyl chloride (22 mg, 0.29 mmol) was added to an ice cooledsolution of the amine of example 1 (100 mg, 0.29 mmol) indichloromethane (50 ml) and stirred at room temperature for 2 hours. Thedichloromethane was evaporated off under reduced pressure and theresidue purified by chromatography on silica gel using methanol andammonium hydroxide in dichloromethane (5:0.5:95) as eluant to give thetitle compound as a brown foam (102 mg).

[0732] APCl MS m/z 389 [MH]⁺, 412 [MNa]⁺

[0733]¹H NMR (400 MHz, CDCl₃): δ 1.50-2.28 (m, 7H, rotamers), 3.01 (brs,2H), 3.10 (m, 1H), 4.00-5.00 (m, 6H, rotamers), 6.61 (m, 1H), 6.68 (m,1H), 7.50 (m, 3H), 7.61 (m, 2H), 8.18 (m, 1H)

EXAMPLE 48-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[0734]

[0735] Toluene-4-sulfonic acid (100 mg, 0.58 mmol) was added to asolution of the oxadiazole of preparation 14 (4.65 g, 12 mmol) andheated to 140° C. for 18 hours. The mixture was cooled and purified bychromatography on silica gel using methanol and ammonium hydroxide indichloromethane (5:0.5:95) as eluant to give the title compound (2.0 g)as an off-white solid.

[0736] APCl MS m/z 381 [MH]⁺, 403 [MNa]⁺

[0737]¹H NMR (400 MHz, CDCl₃): δ 1.80-2.20 (m, 4H), 2.95 (m, 2H), 3.14(m, 1H), 3.68 (s, 2H), 3.92 (s, 2H), 4.36 (m, 2H), 6.60 (m, 1H), 6.67(d, 1H), 7.35 (d, 1H), 7.50 (m, 3H), 8.17 (d, 1H)

[0738] Found; C, 59.90; H, 5.48; N, 20.50; C₂₀H₂₁N₆Cl 0.33CH₂Cl₂requires; C, 59.72; H, 5.34; N, 20.55%.

EXAMPLE 4b8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro4H-2,3,5,10b-tetraaza-benzo[e]azulene

[0739]

[0740] Trifluoroacetic acid (2.9 ml, 38 mmol) was added to atetrahydrofuran solution of the oxadiazole of preparation 14b (10 g, 25mmol) and heated to 65-67° C. for 6 hours. The reaction mixture wascooled and adjusted to pH 7 with sodium hydroxide (5M) before vacuumdistillation to ethyl acetate.

[0741] The reaction mixture was then adjusted to pH 10 with furthersodium hydroxide (5M) followed by cooling to 10° C. for 1 hour. Theproduct was isolated by filtration and then reslurried in water beforere-filtering. The product, a white solid, was dried under vacuum (7.75g).

[0742] APCl MS m/z 381 [MH]⁺, 403 [MNa]⁺

[0743]¹H NMR (400 MHz, CDCl₃): δ 1.80-2.20 (m, 4H), 2.95 (m, 2H), 3.14(m, 1H), 3.68 (s, 2H), 3.92 (s, 2H), 4.36 (m, 2H), 6.60 (m, 1H), 6.67(d, 1H), 7.35 (d, 1H), 7.50 (m, 3H), 8.17 (d, 1H)

[0744] Found; C, 59.90; H, 5.48; N, 20.50; C₂₀H₂₁N₆Cl 0.33CH₂Cl₂requires; C, 59.72; H, 5.34; N, 20.55%.

EXAMPLE 58-Chloro-5-methyl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulenetrihydrochloride

[0745]

[0746] Formaldehyde (37% w/v aqueous, 0.1 ml, 1.2 mmol) was added to asolution of the amine of example 4 (200 mg, 0.53 mmol) indichloromethane (5 ml). The mixture was stirred at room temperature for0.25 hours before sodium triacetoxyborohydride (500 mg, 2.4 mmol) wasadded, and the reaction mixture was stirred for a further 18 hours. Thereaction mixture was partitioned between 2N aqueous sodium hydroxidesolution (10 ml) and dichloromethane (10 ml). The organic layer wasevaporated under reduced pressure and purified by chromatography onsilica gel using methanol in dichloromethane (5:95) as eluant. Theresidue was dissolved in dichloromethane (2 ml) and hydrochloric acid(1M in diethyl ether, 2 ml) was added. The solvent was evaporated underreduced pressure to give the title compound as a brown foam (96 mg).

[0747] APCl MS m/z 395 [MH]⁺, 417 [MNa]⁺

[0748]¹H NMR (400 MHz, CD₃OD): δ 2.00 (m, 2H), 2.27 (m, 1H), 2.58 (m,1H), 3.11 (s, 3H) 3.66 (m, 1H), 3.62 (m, 2H), 4.21 (m, 4H), 4.40 (m,1H), 4.55 (m, 1H), 7.00 (t, 1H), 7.44 (d, 1H), 7.88 (m, 2H), 7.92 (m,2H), 8.06 (t, 1H)

[0749] Found; C, 44.30; H, 5.52; N, 14.65; C₂₁H₂₃N₆Cl 0.33CH₂Cl₂.3HCl.2.5H₂O requires; C 44.37; H, 5.53; N, 14.53%.

EXAMPLE 5b8-Chloro-5-methyl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[0750]

[0751] To a solution of the thioamide of preparation 84 (80 mg, 0.35mmol) in butan-1-ol was added the hydrazide of preparation 1 (78 mg,0.35 mmol) and the mixture was heated to 100° C. for 20 hours. Thereaction mixture was evaporated under reduced pressure and the residuewas purified by column chromatography on silica gel usingdichloromethane: Methanol: 0.880 ammonia (90:10:1) as eluant, to affordthe title compound as a brown foam (90 mg).

[0752]¹H NMR (400 MHz, CDCl₃): δ 2.00 (m, 4H), 2.45 (s, 3H), 3.96 (t,2H), 3.15 (m, 1H), 3,36 (m, 1H), 3.64 (m, 2H), 4.36 (m, 2H), 6.58 (m,1H), 6.65 (d, 1H), 7.32 (d, 1H), 7.46 (t, 1H), 7.52 (m, 2H), 8.18 (t,1H)

[0753] APCl MS m/z 395 [MH]⁺, 417 [Mna]⁺

EXAMPLE 5c8-Chloro-5-methyl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulenetrihydrochloride

[0754]

[0755] Acetic acid (3 ml, 52 mmol) was added to a solution of the amineof example 4b (10 g, 26 mmol) in dichloromethane (100 ml) followed byformaldehyde (37% w/v aqueous, 3.2 ml, 39 mmol). In a separate vesselsodium triacetoxyborohydride (6.7 g, 31 mmol) was slurried indichloromethane and cooled to <10° C. The imine solution was then addeddropwise to the cold slurry over 15 minutes. The reaction mixture wasstirred at room temperature for 0.5 hours, after which time the reactionmixture was partitioned between 2N aqueous sodium hydroxide solution anddichloromethane. The organic phase was then washed three times with a50% aqueous solution of sodium metabisulfite, followed by a final waterwash. The dichloromethane solution was distilled to half volume beforeadding EtOAc and further distilled to remove the remainingdichloromethane. EtOH was added and the reaction mixture heated for afurther 0.5 hours, before cooling to 10° C. and isolating the product asa white solid. The solid was dried under vacuum at 50° C. for 16 hoursto afford the title compound (7.48 g).

[0756] APCl MS m/z 395 [MH]⁺, 417 [MNa]⁺

[0757]¹H NMR (400 MHz, CD₃OD): δ 2.00 (m, 2H), 2.27 (m, 1H), 2.58 (m,1H), 3.11 (s, 3H), 3.36 (m, 1H), 3.62 (m, 2H), 4.21 (m, 4H), 4.40 (m,1H), 4.55 (m, 1H), 7.00 (t, 1H), 7.44 (d, 1H), 7.88 (m, 2H), 7.92 (m,2H), 8.06 (t, 1H)

[0758] Found; C, 44.30; H, 5.52; N, 14.65; C₂₁H₂₃N₆Cl 0.33CH₂Cl₂. 3HCl.2.5H₂O requires; C, 44.37; H, 5.53; N, 14.53%.

EXAMPLE 68-Chloro-5-isopropyl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulenetrihydrochloride

[0759]

[0760] Acetone (0.1 ml, 1.36 mmol) was added to a solution of the amineof example 4 (200 mg, 0.53 mmol) in dichloromethane (5 ml). The mixturewas stirred at room temperature for 0.25 hours before sodiumtriacetoxyborohydride (500 mg, 2.4 mmol) was added, and the reactionmixture stirred for a further 18 hours. The reaction mixture waspartitioned between 2N aqueous sodium hydroxide solution (10 ml) anddichloromethane (10 ml). The organic layer was evaporated under reducedpressure and purified by chromatography on silica gel using methanol indichloromethane (5:95) as eluant. The residue was dissolved indichloromethane (2 ml) and hydrochloric acid (1M in diethyl ether, 2 ml)was added. The solvent was evaporated under reduced pressure to give thetitle compound as a brown foam (161 mg).

[0761] APCl MS m/z 423 [MH]⁺, 445 [MNa]⁺

[0762]¹H NMR (400 MHz, CD₃OD): δ 1.57 (m, 6H), 2.00 (m, 2H), 2.24 (m,1H), 2.58 (m, 1H), 3.38 (m, 1H), 3.58 (m, 1H), 3.70 (m, 1H), 3.86 (m,1H), 4.23 (m, 3H), 4.40 (m, 1H), 4.62 (m, 1H), 5.00 (m, 1H), 7.00 (m,1H), 7.43 (m, 1H), 7.80-8.06 (m, 5H)

[0763] Found; C, 46.51; H, 5.98; N, 13.96; C₂₃H₂₇N₆Cl 0.28CH₂Cl₂. 3HCl.2.5H₂O requires; C, 46.51; H, 5.96; N, 13.98%.

EXAMPLE 78-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5-(tetrahydro-pyran-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[0764]

[0765] Tetrahydro-pyran-4-one (68 mg, 0.68 mmol) was added to a solutionof the amine of example 4 (130 mg, 0.34 mmol) in dichloromethane (5 ml).The mixture was stirred at room temperature for 0.25 hours before sodiumtriacetoxyborohydride (217 mg, 1.0 mmol) was added, and the reactionmixture was stirred for a further 18 hours. Furthertetrahydro-pyran-4-one (68 mg, 0.68 mmol) and sodiumtriacetoxyborohydride (217 mg, 1.0 mmol) were added and the reactionmixture was heated to 40° C. for 24 hours. The reaction mixture waspartitioned between 2N aqueous sodium carbonate solution (10 ml) andethyl acetate (50 ml). The organic layer was washed three times with 2Naqueous sodium carbonate solution (10 ml), once with saturated aqueousbrine, and then dried over magnesium sulphate before filtering andevaporating the filtrate under reduced pressure. The residue waspurified by chromatography on silica gel using a gradient of ethylacetate in pentane (0% to 30%) as eluant, followed by chromatography onsilica gel using a gradient of methanol in dichloromethane (0% to 5%) aseluant, to afford the title compound as a brown foam (80 mg).

[0766] APCl MS m/z 465 [MH]⁺, 487 [MNa]⁺

[0767]¹H NMR (400 MHz, CDCl₃): δ 1.57-175 (m, 4H), 1.75-2.20 (m, 6H),2.72 (m, 1H), 2.98 (t, 2H), 3.16 (m, 1H), 3.39 (t, 2H), 3.40-3.60 (m,2H), 3.60-4.10 (m, 2H), 4.02 (d, 2H), 4.34 (d, 2H), 6.61 (dd, 1H), 6.69(d, 1H), 7.33 (d, 1H), 7.45-7.59 (m, 3H), 8.17 (d, 1H).

EXAMPLE 81-[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-ethanonedihydrochloride

[0768]

[0769] Acetyl chloride (0.1 ml, 1.4 mmol) was added to an ice cooledsolution of the amine of example 4 (200 mg, 0.53 mmol) indichloromethane (5 ml) and stirred at room temperature for 20 hours.Dichloromethane was evaporated off under reduced pressure and theresidue purified by chromatography on silica gel using methanol indichloromethane (5:95) as eluant. The residue was dissolved indichloromethane (2 ml) and hydrochloric acid (1M in diethyl ether, 2 ml)was added, and the solvents evaporated under reduced pressure to givethe title compound as a brown foam (110 mg).

[0770] ESI MS m/z 423 [M+H]⁺

[0771]¹H NMR (400 MHz, CD₃OD): δ 1.95-2.40 (m, 7H, rotamers), 3.40-3.55(m, 2H), 3.80 (m, 1H), 4.20-4.90 (m, 4H, rotamers), 4.82 (s, 2H), 7.02(t, 1H), 7.46 (d, 1H), 7.80 (m, 1H), 7.91 (t, 1H), 7.95-8.00 (m, 2H),8.07 (t, 1H)

[0772] Found C, 45.94%, H, 5.77%, N, 14.35%;C₂₂H₂₃ClN₆O.2HCl.0.40CH₂Cl₂.3.07H₂O requires C, 45.98%, H, 5.50%, 14.36%

EXAMPLE 9[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-cyclopropyl-methanonedihydrochloride

[0773]

[0774] The title compound was prepared from Cyclopropanecarbonylchloride and the amine of example 4, in 50% yield, using the proceduredescribed in example 8.

[0775] ESI MS m/z 449 [M+H]⁺

[0776]¹H NMR (400 MHz, CD₃OD): δ 0.83-1.00 (m, 4H), 1.80-2.50 (m, 4H,rotamers), 3.40-3.60 (m, 2H), 3.89 (bt, 1H), 4.20-5.0 (m, 3H, rotamers),4.86 (s, 2H), 7.04 (t, 1H), 7.26 (d, 1H), 7.82 (bd, 1H), 7.90-8.00 (m,3H), 8.08 (t, 1H)

EXAMPLE 101-[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-2,2-dimethyl-propan-1-onedihydrochloride

[0777]

[0778] The title compound was prepared from 2,2-Dimethyl-propionylchloride and the amine of example 4, in 54% yield, using the proceduredescribed in example 8.

[0779] APCl MS m/z 465 [M+H]⁺

[0780]¹H NMR (400 MHz, CD₃OD): δ 1.40 (s, 9H), 1.80-2.60 (m, 4H,rotamers), 3.40-3.60 (m, 2H), 3.88 (bt, 1H), 4.10-5.00 (m, 4H,rotamers), 4.85 (s, 2H), 7.04 (t, 1H), 7.47 (d, 1H), 7.80-7.86 (m, 2H),7.94 (d, 1H), 7.99 (d, 1H), 8.08 (t, 1H)

EXAMPLE 118-Chloro-5-methanesulfonyl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[0781]

[0782] Methanesulfonyl chloride (0.1 ml, 1.29 mmol) was added to an icecooled solution of the amine of example 4 (200 mg, 0.53 mmol) indichloromethane (5 ml) and stirred at room temperature for 20 hours. Thedichloromethane was evaporated off under reduced pressure and theresidue purified by chromatography on silica gel using methanol indichloromethane (5:95) as eluant, to afford the title compound as abrown foam (71 mg).

[0783] APCl MS m/z 459 [M+H]⁺, 481 [M+Na]⁺

[0784] Found C, 52.98%, H, 5.05%, N, 17.20%; C₂₁H₂₃ClN₆O₂S.0.25CH₂Cl₂requires C, 5315%, H, 4.93%, 17.50%

EXAMPLE 128-Chloro-1-(1-pyrimidin-2-yl-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[0785]

[0786] Toluene-4-sulfonic acid (5 mg, 0.03 mmol) was added to a solutionof the oxadiazole of preparation 15 (2.34 g, 5.9 mmol) and heated to140° C. for 18 hours. The mixture was cooled and purified bychromatography on silica gel using methanol and ammonium hydroxide indichloromethane (5:0.5:95) as eluant to afford the title compound (1.12g) as an off-white solid.

[0787] ESI MS m/z 382 [M+H]⁺

[0788]¹H NMR (400 MHz, CDCl₃): δ 1.60-2.20 (m, 4H), 2.95 (bt, 2H), 3.10(m, 1H), 3.63 (s, 2H), 3.70-4.00 (m, 2H), 4.75 (d, 2H), 6.43 (t, 1H),7.26 (d, 1H), 7.40-7.52 (m, 2H), 8.22 (d, 2H)

[0789] Found C, 57.24%, H, 5.31%, N, 24.10%; C₁₉H₂₀ClN₇.0.25CH₂Cl₂requires C, 57.36%, H 5.13%, 24.32%

EXAMPLE 138-Chloro-5-methyl-1-(1-pyrimidin-2-yl-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[0790]

[0791] Formaldehyde (37% w/v aqueous, 0.1 ml, 1.2 mmol) was added to asolution of the amine of example 12 (100 mg, 0.26 mmol) indichloromethane (5 ml). The mixture was stirred at room temperature for0.25 hours before sodium triacetoxyborohydride (111 mg, 0.53 mmol) wasadded, and the reaction mixture was stirred for a further 18 hours. Themixture was partitioned between 2N aqueous sodium hydroxide solution (10ml) and dichloromethane (10 ml). The organic layer was evaporated underreduced pressure and purified by chromatography on silica gel usingmethanol in dichloromethane (5:95) as eluant to afford the titlecompound as a brown foam (66 mg).

[0792] ESI MS m/z 382 [M+Na]⁺

[0793]¹H NMR (400 MHz, CDCl₃): δ 1.50-2.20 (m, 4H), 2.45 (s, 3H), 2.98(bt, 2H), 3.10 (bt, 1H), 3.20-3.90 (m, 3H), 4.77 (s, 2H), 6.45 (s, 1H),7.32 (d, 1H), 7.46-7.53 (m, 2H), 8.26 (d, 2H)

[0794] Found C, 59.12%, H, 5.50%, N, 24.00%; C₂₀H₂₂ClN₇.0.15CH₂Cl₂requires C, 59.23%, H 5.66%, N, 23.99%

EXAMPLE 148-Chloro-5-isopropyl-1-(1-pyrimidin-2-yl-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[0795]

[0796] The title compound was prepared from acetone and the amine ofexample 12, in 65% yield, using the procedure described in example 13.

[0797] ESI MS m/z 382 [M+H]⁺

[0798]¹H NMR (400 MHz, CDCl₃): δ 1.20 (d, 6H), 1.60-2.10 (m, 4H),2.90-3.07 (m, 3H), 3.18 (t, 1H), 3.30-4.00 (m, 4H), 4.78 (d, 2H), 6.47(t, 1H), 7,29 (d, 1H), 7.48-7.58 (m, 2H), 8.30 (d, 2H)

[0799] Found C, 60.55%, H, 6.24%, N, 21.73%; C₂₂H₂₆ClN₇.0.22CH₂Cl₂requires C, 60.17%, H, 6.03%, N, 22.11%.

EXAMPLE 158-Chloro-5-methanesulfonyl-1-(1-pyrimidin-2-yl-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[0800]

[0801] The title compound was prepared from the amine of example 12, in69% yield, using the procedure described in example 11.

[0802] APCl MS m/z 460 [M+H]⁺, 482 [M+Na]⁺

[0803]¹H NMR (400 MHz, CDCl₃): δ 1.40-2.40 (m, 6H), 2.95 (s, 3H),2.90-4.20 (m, 5H), 4.40-5.30 (m, 4H), 6.52 (t, 1H), 7.40 (d, 1H),7.60-7.70 (m, 2H), 8.32 (d, 2H)

EXAMPLE 16 [8-Chloro-1-(1-pyrimidin-2-yl-piperidin-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-cyclopropyl-methanone

[0804]

[0805] The title compound was prepared as an off-white foam fromcyclopropanecarbonyl chloride and the amine of example 12, in 69% yield,using the procedure described in example 3.

[0806] APCl MS m/z 472 [M+Na]⁺

[0807]¹H NMR (400 MHz, CDCl₃): δ 0.86 (m, 2H), 1.04 (m, 2H), 1.40-2.40(m, 6H), 2.70-3.20 (m, 3H), 4.40-5.80 (m, 5H), 6.61 (t, 1H), 7.39 (d,1H), 7.52-7.65 (m, 2H), 8.32 (d, 2H)

EXAMPLE 17 1-[8-Chloro-1-(1-pyrimidin-2-yl-piperidin-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-2,2-dimethyl-propan-1-one

[0808]

[0809] The title compound was prepared from 2,2-Dimethyl-propionylchloride and the amine of example 12, in 42% yield, using the proceduredescribed in example 3.

[0810] APCl MS m/z 466 [M+H]⁺

[0811]¹H NMR (400 MHz, CDCl₃): δ 1.38 (s, 9H), 1.40-2.40 (m, 7H),2.90-3.10 (m, 2H), 3.17 (m, 1H), 4.60-5.00 (m, 2H), 5.27 (s, 2H), 6.58(t, 1H), 7.35 (d, 1H), 7.54-7.68 (m, 2H), 8.29 (d, 1H)

EXAMPLE 181-[8-Chloro-1-(1-pyrimidin-2-yl-piperidin-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-ethanone

[0812]

[0813] The title compound was prepared from acetyl chloride and theamine of example 12, in 37% yield, using the procedure described inexample 3.

[0814] APCl MS m/z 424 [M+H]⁺

[0815]¹H NMR (400 MHz, CDCl₃): δ 1.40-2.50 (m, 10H), 2.70-3.30 (m, 4H),4.70-4.90 (m, 2H), 6.52 (t, 1H), 7.38 (d, 1H), 7.54-7.64 (m, 2H), 8.33(d, 2H)

EXAMPLE 198-Chloro-1-(6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulene

[0816]

[0817] 2-Chloro-6-trifluoromethyl-pyridine (55 mg, 0.30 mmol) andpotassium carbonate (41 mg, 0.30 mmol) were added to a solution of theamine of preparation 29 (45 mg, 0.15 mmol) in N,N-dimethylformamide (2ml). The mixture was heated at 100° C. for 18 hours before evaporationunder reduced pressure. The residue was purified by chromatography onsilica gel using methanol and ammonium hydroxide in dichloromethane(5:0.5:95) as eluant to afford the title compound (30 mg), as a brownfoam.

[0818] APCl MS m/z 450 [M+H]⁺, 472 [M+Na]⁺

[0819]¹H NMR (400 MHz, CD₃OD): δ 1.88-2.06 (m, 4H), 3.01 (bt, 2H), 3.40(m, 1H), 4.44 (bs, 2H), 4.51 (d, 2H), 4.59 (s, 2H), 6.94 (d, 1H), 7.02(d, 1H), 7.68 (t, 1H), 7.74-7.78 (m, 4H).

EXAMPLE 204-(8-Chloro-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulen-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-carbonitrile

[0820]

[0821] The title compound was prepared from6-Chloro-pyridine-2-carbonitrile and the amine of preparation 29, in 61%yield, using the procedure described in example 19.

[0822] APCl MS m/z 407 [M+H]⁺, 429 [M+Na]⁺

[0823]¹H NMR (400 MHz, CD₃OD): δ 1.86-2.08 (m, 4H), 3.03 (bt, 2H), 3.44(m, 1H), 4.46 (m, 4H), 4.59 (s, 2H), 7.03 (d, 1H), 7.11 (d, 1H), 7.62(dd, 1H), 7.72-7.78 (, 3H)

[0824] Found C, 61.31%, H, 4.73%, N, 20.38%; C₂₁H₁₉ClN₆O.0.25H₂Orequires C, 61.31%, H, 4.78%, N, 20.43%

EXAMPLE 214-(8-Chloro-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulen-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-carboxylicacid amide

[0825]

[0826] Powdered potassium hydroxide (46 mg, 81 mmol) was added to asolution of the carbonitrile of example 20 (110 mg, 0.27 mmol) in2-Methyl-propan-2-ol (6 ml). The mixture was heated at 100° C. for 18hours before evaporation under reduced pressure. The residue waspurified by chromatography on silica gel using methanol and ammoniumhydroxide in dichloromethane (5:0.5:95) as eluant, to afford the titlecompound (62 mg), as an off-white solid.

[0827] APCl MS m/z 425 [M+H]⁺, 447 [M+Na]⁺

[0828]¹H NMR (400 MHz, CD₃OD): δ 1.89-2.07 (m, 4H), 3.01 (bt, 2H), 3.42(m, 1H), 4.45 (s, 2H), 4.52 (bd, 2H), 4.60 (s, 2H), 7.02 (d, 1H), 7.38(d, 1H), 7.67 (dd, 1H), 7.72-7.78 (m, 4H)

EXAMPLE 2213-Chloro-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-2,4,5,8-tetraaza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),3,5,12,14-pentaene

[0829]

[0830] Toluene-4-sulfonic acid (50 mg, 0.3 mmol) was added to a solutionof the oxadiazole of preparation 41 (1.35 g, 3.3 mmol) and heated to140° C. for 2 hours. The mixture was cooled and purified bychromatography on silica gel using ethyl acetate followed by methanoland ammonium hydroxide in dichloromethane (5:0.5:95) as eluant, toafford the title compound (273 mg) as an off-white solid.

[0831] APCl MS m/z 398 [M+H]⁺

[0832]¹H NMR (400 MHz, CDCl₃): δ 1.42 (bd, 1H), 1.65 (dq, 1H), 2.05 (dt,1H), 2.16 (bd, 1H), 2.32 (dq, 1H), 2.63-2.77 (m, 2H), 2.79-2.94 (m, 2H),2.95 (m, 1H), 3.10 (d, 1H), 3.46 (dt, 1H), 4.18 (bd, 1H), 4.38 (bd, 1H),4.41 (d, 1H), 6.59 (dd, 1H), 6.65 (d, 1H), 7.18 (d, 1H), 7.38-7.42 (m,2H), 7.57 (t, 1H), 8.17 (d, 1H)

[0833] Found C, 62.41%, H, 5.98%, N, 20.45%; C₂₁H₂₃ClN₆.0.12CH₂Cl₂requires C, 62.72%, H, 5.78%, N, 20.75%

EXAMPLE 231-[13-Chloro-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-2,4,5,8-tetraaza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),3,5,12,14-pentaen-8-yl]-ethanone

[0834]

[0835] Acetic anhydride (35 □l, 0.37 mmol) was added to a solution ofthe amine of example 22 (120 mg, 0.30 mmol) and triethylamine indichloromethane (5 ml) and stirred at room temperature for 2 hours. Thedichloromethane was evaporated off under reduced pressure and theresidue was purified by chromatography on silica gel using methanol andammonium hydroxide in dichloromethane (5:0.5:95) as eluant, to affordthe title compound as a white solid (120 mg).

[0836] APCl MS m/z 437 [M+H]⁺, 459 [M+Na]⁺

[0837]¹H NMR (400 MHz, CDCl₃): δ 1.44 (bd, 1H), 1.63 (m, 1H), 2.16 (m,2H), 2.10-2.22 (m, 2H), 2.28 (dt, 1H), 2.44 (s, 3H), 2.63-2.80 (m, 2H),2.83-3.05 (m, 3H), 3.66 (d, 1H), 4.15 (bd, 1H), 4.41 (bd, 1H), 4.94 (dd,1H), 5.06 (d, 1H), 6.59 (t, 1H), 6.63 (d, 1H), 7.17 (d, 1H), 7.38-7.50(m, 3H), 8.14 (d, 1H)

[0838] Found C, 61.92%, H, 5.93%, N, 18.38%; C₂₁H₂₃ClN₆.0.60H₂O requiresC, 61.70, H, 5.90%, N, 18.77%

EXAMPLE 2413-Chloro-8-methyl-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-2,4,5,8-tetraaza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),3,5,12,14-pentaene

[0839]

[0840] The title compound was prepared from the amine of example 22, in78% yield, using the procedure described in example 2.

[0841] APCl MS m/z 409 [M+H]⁺, 431 [M+Na]⁺

[0842]¹H NMR (400 MHz, CDCl₃): δ 1.41 (bd, 1H), 1.62 (dq, 1H), 2.14 (bd,1H), 2.23-2.32 (m, 2H), 2.37 (s, 3H), 2.55 (dd, 1H), 2.66-2.78 (m, 2H),2,88 (m, 1H), 2.96 (dt, 1H), 3.20 (d, 1H), 3.26 (dd, 1H), 4.15 (d, 2H),4.35 (bd, 1H), 6.55 (dd, 1H), 6.62 (d, 1H), 7.14 (d, 1H), 7.32-7.39 (m,2H), 7.41 (t, 1H), 8.12 (d, 1H)

EXAMPLE 253-(1-Pyrimidin-2-yl-piperidin-4-yl)-8-oxa-2,4,5-triaza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),3,5,12,14-pentaene

[0843]

[0844] The title compound was prepared from the oxadiazole ofpreparation 24, in 50% yield, using the procedure described in example22.

[0845] ESI MS m/z 364 [M+H]⁺

[0846]¹H NMR (400 MHz, CDCl₃): δ 1.48 (bd, 1H), 1.65 (dq, 1H), 2.20 (bd,1H), 2.31 (dq, 1H), 2.44 (m, 1H), 2.83-2.95 (m, 2H), 3.01 (m, 1H), 3.11(dt, 1H), 3.50 (q, 1H), 3.92 (d, 1H), 4.26 (m, 1H), 4.60 (d, 1H), 4.92(d, 1H), 5.08 (d, 1H), 6.50 (t, 1H), 7.24 (t, 1H), 7.40 (t, 1H), 7.46(d, 1H), 7.53 (t, 1H), 8.32 (d, 2H)

EXAMPLE 268-Chloro-1-(1-pyrimidin-2-yl-piperidin-4-yl)-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulene

[0847]

[0848] The title compound was prepared from the oxadiazole ofpreparation 23, in 70% yield, using the procedure described in example22.

[0849] ESI MS m/z 383 [M+H]⁺

[0850]¹H NMR (400 MHz, CDCl₃): δ 1.92-2.13 (m, 4H), 3.07 (t, 2H), 3.12(m, 1H), 4.39 (s, 2H), 4.66 (s, 2H), 4.82 (m, 2H), 6.53 (t, 1H), 7.39(d, 1H), 7.57-7.63 (m, 2H), 8.33 (d, 2H)

EXAMPLE 27 b13-Chloro-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-8-oxa-2,4,5-triaza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),3,5,12,14-pentaene

[0851]

[0852] The title compound was prepared from the oxadiazole ofpreparation 22, in 40% yield, using the procedure described in example22.

[0853] APCl MS m/z 396 [M+H]⁺

[0854]¹H NMR (400 MHz, CDCl₃): δ 1.44 (bd, 1H), 1.66 (dq, 1H), 2.17 (bd,1H), 2.36 (dq, 1H), 2.43 (m, 1H), 2.72-2.85 (m, 2H), 2.89-3.03 (m, 2H),3.55 (t, 1H), 3.97 (d, 1H), 4.14-4.26 (m, 2H), 4.40 (bd, 1H), 5.07 (d,1H), 6.59 (dd, 1H), 6.64 (d, 1H), 7.19 (d, 1H), 7.38-7.48 (m, 3H), 8.15(d, 1H)

[0855] Found C, 62.84%, H, 5.54%, N, 17.34%; C₂₁H₂₂ClN₅O.0.08CH₂Cl₂requires C, 62.88%, H, 5.55%, N, 17.39%.

EXAMPLE 283-(3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-8-oxa-2,4,5-triaza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),3,5,12,14-pentaenedihydrochloride

[0856]

[0857] The title compound was prepared from the oxadiazole ofpreparation 21, in 49% yield, using the procedure described in example22. The dihydrochloride salt was prepared using the procedure describedin example 8.

[0858] APCl MS m/z 362 [M+H]⁺

[0859]¹H NMR (400 MHz, CD₃OD): δ 1.67-1.81 (m, 2H), 2.32 (dq, 1H),2.47-2.57 (m, 2H), 3.11 (dd, 1H), 3.25 (dt, 1H), 3.33 (m, 2H), 3.45-3.62(m, 3H), 4.07-4.16 (m, 2H), 4.30 (m, 1H), 4.40 (bd, 1H), 5.07 (d, 1H),7.00 (t, 1H), 7.40 (d, 1H), 7.60-7.66 (m, 2H), 7.69-7.78 (m, 2H), 7.96(d, 1H), 8.06 (t, 1H).

EXAMPLE 298-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulene

[0860]

[0861] The title compound was prepared from the oxadiazole ofpreparation 20, in 60% yield, using the procedure described in example22.

[0862] APCl MS m/z 382 [M+H]⁺

[0863]¹H NMR (400 MHz, CDCl₃): δ 1.97 (bd, 2H), 2.09 (m, 2H), 2.98 (dt,2H), 3.17 (m, 1H), 4.32-4.40 (m, 4H), 4.64 (s, 2H), 6.59 (dd, 1H), 6.64(d, 1H), 7.39 (d, 1H), 7.45 (t, 1H), 7.56-7.61 (m, 2H), 8.17 (d, 1H).

[0864] Found C, 60.19%, H, 5.17%, N, 17.31%; C₂₁H₂₂ClN₅O.0.27CH₂Cl₂requires C, 60.14%, H, 5.11%, N, 17.30%

EXAMPLE 307-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulenedihydrochloride

[0865]

[0866] The title compound was prepared from the oxadiazole ofpreparation 17, in 21% yield, using the procedure described in example22. The dihydrochloride salt was prepared using the procedure describedin example 8.

[0867] APCl MS m/z 382 [M+H]⁺

[0868]¹H NMR (400 MHz, CD₃OD): δ 2.10 (m, 2H), 2.30 (m, 2H), 3.50 (bt,2H), 3.74 (m, 1H), 4.32 (m, 2H), 4.93 (s, 2H), 7.00 (t, 1H), 7.46 (d,1H), 7.77-7.95 (m, 3H), 8.00 (dd, 1H), 8.09 (t, 1H).

EXAMPLE 311-(3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulene

[0869]

[0870] The title compound was prepared from the oxadiazole ofpreparation 16, in 41% yield, using the procedure described in example22.

[0871] APCl MS m/z 348 [M+H]⁺

[0872]¹H NMR (400 MHz, CDCl₃): δ 1.98 (bd, 2H), 2.12 (m, 2H), 2.97 (t,2H), 3.24 (m, 1H), 4.53 (d, 2H), 4.45 (s, 2H), 4.65 (s, 2H), 6.59 (dd,1H), 6.69 (d, 1H), 7.38-7.49 (m, 2H), 7.53-7.65 (m, 3H), 8.18 (d, 1H)

[0873] Found C, 64.55%, H, 5.84%, N, 17.92%;C₂₀H₂₁N₅O.0.40CH₂Cl₂.0.08C₈H₁₀ requires C, 64.82%, H, 5.84%, N, 17.96%

EXAMPLE 328-Methoxy-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulenedihydrochloride

[0874]

[0875] The title compound was prepared from the oxadiazole ofpreparation 19, in 68% yield, using the procedure described in example22. The dihydrochloride salt was prepared using the procedure describedin example 8.

[0876] ESI MS m/z 379 [M+H]⁺

[0877]¹H NMR (400 MHz, CD₃OD): δ 2.08 (bq, 2H), 2.30 (bd, 2H), 3.49 (t,2H), 3.85 (m, 1H), 3.95 (s, 3H), 4.32 (bd, 2H), 4.59 (s, 2H), 4.68 (s,2H), 7.03 (t, 1H), 7.31-7.35 (m, 2H), 7.45 (d, 1H), 7.80, (d, 1H),7.97(d, 1H), 8.08 (t, 1H).

EXAMPLE 338-Fluoro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulene

[0878]

[0879] The title compound was prepared from the oxadiazole ofpreparation 31, in 62% yield, using the procedure described in example22.

[0880] APCl MS m/z 366 [M+H]⁺

[0881]¹H NMR (400 MHz, CDCl₃): δ 1.90-2.16 (m, 4H), 2.97 (dt, 2H), 3.16(m, 1H), 4.28-4.40 (m, 4H), 4.63 (s, 2H), 6.58 (dd, 1H), 6.66 (d, 1H),7.24-7.35 (m, 2H), 7.40-7.52 (m, 2H), 8.15 (d, 1H)

[0882] Found C, 64.47%, H, 5.56%, N, 18.50%;C₂₀H₂₀FN₅O.0.07CH₂Cl₂.0.07EtOAc requires C, 64.74%, H, 5.53%, N, 18.55%.

EXAMPLE 348,9-Difluoro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulenedihydrochloride

[0883]

[0884] The title compound was prepared from the oxadiazole ofpreparation 33, in 44% yield, using the procedure described in example22. The dihydrochloride salt was prepared using the procedure describedin example 8.

[0885] APCl MS m/z 384 [M+H]⁺

[0886]¹H NMR (400 MHz, CD₃OD): δ 2.00-2.13 (m, 2H), 2.18-2.37 (m, 2H),3.52 (dt, 2H), 4.33 (bd, 2H), 4.58 (s, 2H), 4.68 (s, 2H), 7.02 (t, 1H),7.47 (d, 1H), 7.81 (dd, 1H), 7.94-8.02 (m, 2H), 8.06 (t, 1H)

[0887] Found C, 49.58%, H, 5.01%, N, 14.25%;C₂₀H₁₉F₂N₅O₁.2HCl.0.30CH₂Cl₂.0.58H₂O requires C, 49.53%, H, 4.66%, N,14.23%

EXAMPLE 359-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulenedihydrochloride

[0888]

[0889] The title compound was prepared from the oxadiazole ofpreparation 18, in 54% yield, using the procedure described in example22. The dihydrochloride salt was prepared using the procedure describedin example 8.

[0890] APCl MS m/z 383 [M+H]⁺

[0891]¹H NMR (400 MHz, CD₃OD): δ 2.10 (m, 2H), 2.35 (m, 2H), 3.55 (dt,2H), 4.00 (bd, 1H), 4.35 (m, 2H), 4.65 (s, 2H), 4.80 (s, 2H), 7.02 (m,1H), 7.45 (m, 1H), 7.81 (s, 2H), 8.00 (m, 3H)

EXAMPLE 361-(3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-8-trifluoromethoxy-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulene

[0892]

[0893] The title compound was prepared from the oxadiazole ofpreparation 36, in 44% yield, using the procedure described in example22.

[0894] APCl MS m/z 432 [M+H]⁺

[0895]¹H NMR (400 MHz, CDCl₃): δ 1.99 (m, 2H), 2.13 (m, 2H), 3.00 (dt,2H), 3.17 (m, 1H), 4.37 (d, 2H), 4.42 (s, 2H), 4.66 (s, 2H), 6.60 (dd,1H), 6.68 (d, 1H), 7.40-7.52 (m, 4H), 8.16 (d, 1H)

[0896] Found C, 58.16%, H, 4.77%, N, 15.84%; C₂₁H₂₀F₃N₅O₂ requires C,58.47%, H, 4.67%, N, 16.23%

EXAMPLE 378-Methyl-1-(3,4,5,6-tetrahydro-2H-[1,2i]bipyridinyl-4-yl)-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulene

[0897]

[0898] The title compound was prepared from the oxadiazole ofpreparation 37, in 48% yield, using the procedure described in example22.

[0899] APCl MS m/z 362 [M+H]⁺

[0900]¹H NMR (400 MHz, CDCl₃): δ 1.99 (m, 4H), 2.43 (m, 3H), 2.96 (dt,2H), 3.41 (m, 1H), 4.34 (d, 2H), 4.42 (s, 2H), 4.66 (brs, 2H), 6.62 (dd,1H), 6.83 (d, 1H), 7.44-7.60 (m, 3H), 7.63 (d, 1H), 8.06 (d, 1H)

EXAMPLE 381-[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-2-dimethylamino-ethanone

[0901]

[0902] A solution of HBTU (152 mg, 0.38 mmol) in N,N-dimethylacetamide(1.9 ml) was added to a solution of the amine of example 4 (97 mg, 0.26mmol), triethylamine (1.5 μl, cat.) and dimethylamino-acetic acid (36mg, 0.26 mmol) in N,N-dimethylacetamide (2.5 ml) and heated to 50° C.for 2 hours. The mixture was cooled and the solvent evaporated underreduced pressure. The residue was partitioned between dichloromethane(10 ml) and 2M aqueous sodium hydroxide solution (10 ml). The organicphase was dried over magnesium sulphate before being evaporated underreduced pressure and purified by chromatography on silica gel usingmethanol and ammonium hydroxide in dichloromethane (7:1:93) as eluant toafford the title compound (70 mg) as a brown foam.

[0903] APCl MS m/z 466 [M+H]⁺

[0904] Found C, 60.14%, H, 5.93%, N, 20.29%; C₂₄H₂₈ClN₇O.2HCl.0.20CH₂Cl₂requires C, 60.18%, H, 5.93%, N, 20.30%

EXAMPLE 392-Chloro-1-[8-chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-ethanone

[0905]

[0906] Triethylamine (1.37 ml, 9.81 mmol) and chloroacetyl chloride(0.35 ml, 4.35 mmol) were added to a solution of the amine from example4 (1.5 g, 3.95 mmol) in dichloromethane (50 ml), and the reactionstirred at room temperature for 2 hours. TLC analysis showed startingmaterial remained, so additional chloroacetyl chloride (0.35 ml, 4.35mmol) was added and the reaction was stirred for an additional 1.5hours. The mixture was partitioned between dichloromethane and 2N sodiumhydroxide solution and the layers separated. The aqueous phase wasextracted with further dichloromethane and the combined organicsolutions were washed with brine (50 ml), dried over magnesium sulphate,and evaporated under reduced pressure. The residual foam was purified bycolumn chromatography on silica gel using dichloromethane:methanol:0.88ammonia (95:5:0.5) to afford the title compound as a foam, 1.12 g.

[0907]¹H NMR (400 MHz, CDCl₃): δ 1.30-2.60 (m, 4H), 2.84-3.20 (m, 3H),3.40-4.80 (m, 8H), 6.62 (m, 1H), 6.70 (m, 1H), 7.40 (m, 1H), 7.50 (m,1H), 7.61 (m, 2H), 8.18 (m, 1H).

[0908] APCl MS m/z 457 [MH]⁺

[0909] Microanalysis found: C, 55.13; H, 4.81; N, 17.19.C₂₂H₂₂Cl₂N₆O;0.33CH₂Cl₂ requires C, 55.26; H, 4.71; N, 17.31%.

EXAMPLE 402-Azetidin-1-yl-1-[8-chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-ethanone

[0910]

[0911] Potassium carbonate (227 mg, 1.65 mmol) and azetidine (0.06 ml,0.82 mmol) were added to a solution of the chloro compound from example39 (250 mg, 0.55 mol) in N,N-dimethylformamide (5 ml) and the reactionmixture stirred at 70° C. for 18 hours. The reaction was concentratedunder reduced pressure and the residue was partitioned between water (10ml) and ethyl acetate (10 ml), and the layers separated. The aqueousphase was extracted with ethyl acetate (2×10 ml). The combined organicsolutions were washed with water (20 ml) and brine (10 ml), then driedover magnesium sulphate and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (95:5:0.5) to afford the titlecompound as a white foam, 55 mg.

[0912]¹H NMR (400 MHz, CDCl₃): δ 1.68-2.30 (m, 6H), 2.80-3.90 (m, 11H),4.10-4.50 (m, 2H), 5.10-5.55 (m, 2H), 6.60 (dd, 1H), 6.66 (d, 1H), 7.40(dd, 1H), 7.45 (m, 1H), 7.58 (m, 2H), 8.18 (d, 1H).

[0913] APCl MS m/z 478 [MH]⁺

[0914] Microanalysis found: C, 60.26; H, 5.83; N, 19.55.C₂₅H₂₈ClN₇O;0.33CH₂Cl₂ requires C, 60.12; H, 5.71; N, 19.38%.

EXAMPLE 411-[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-2-pyrrolidin-1-yl-ethanone

[0915]

[0916] The title compound was obtained as a pale yellow foam from thechloro compound from example 39 and pyrrolidine, following the proceduredescribed in example 40.

[0917]¹H NMR (400 MHz, CDCl₃): δ 1.54-2.01 (m, 8H), 2.05-4.00 (m, 11H),4.20-4.45 (m, 2H), 5.10-5.58 (m, 2H), 6.60 (m, 1H), 6.66 (d, 1H), 7.40(dd, 1H), 7.44 (m, 1H), 7.56-7.74 (m, 2H), 8.18 (d, 1H).

[0918] APCl MS m/z 492 [MH]⁺

EXAMPLE 42[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-pyrrolidin-3-yl-methanonetrihydrochloride

[0919]

[0920] A solution of hydrochloric acid in dioxan (2.98 ml, 4M) was addedto a solution of the protected amine from preparation 65 (690 mg, 1.10mmol) in dichloromethane (5 ml), and the reaction mixture was stirred atroom temperature for 1 hour. The mixture was evaporated under reducedpressure to give the title compound as a white solid (744 mg).

[0921]¹H NMR (400 MHz, CD₃OD): δ 2.00-2.22 (m 3H), 2.56 (m, 1H),3.38-4.01 (m, 14H), 4.24-4.41 (m, 2H), 7.02 (m, 1H), 7.45 (d, 1H), 7.80(m, 1H), 7.90-8.00 (m, 2H), 8.00-8.10 (m, 2H).

[0922] APCl MS m/z 478 [MH]⁺

EXAMPLES 43 to 49

[0923] The following compounds of general structure:

[0924] were prepared quantitatively from the appropriate protectedamines following the procedure described in example 42. Ex No R¹ FormData 43

Solid ¹H NMR (400MHz, CD₃OD): δ1.88-2.70 (m, 8H), 3.38-3.83 (m, 6H),4.50-5.63 (m, 6H), 7.02 (dd, 1H), 7.45 (d, 1H), 7.81 (m, 2H), 7.90 (m,1H), 7.98 (d, 1H), 8.07 (m, 1H). APCI MS m/z 478 [MH]⁺ 44

Solid ¹H NMR (400MHz, CD₃OD): δ1.80-2.80 (m, 8H), 3.22-3.78 (m, 6H),3.82-5.12 (m, 6H), 7.01 (m, 1H), 7.42 (d, 1H), 7.80 (m, 2H), 7.98 (d,1H), 8.05 (m, 1H). APCI MS m/z 478 [MH]⁺ 45

solid APCI MS m/z 491 [M − H]⁻ 46

White solid ¹H NMR (400MHz, CD₃OD): δ 1.40-2.60 (m, 10H), 3.38-3.83 (m,6H), 3.90-5.60 (m, 6H), 7.02 (m, 1H), 7.45 (m, 1H), 7.79-8.18 (m, 5H).APCI MS m/z 491 [M − H]⁻ 47

White solid ¹H NMR (400MHz, CD₃OD): δ 1.40-2.70 (m, 10H), 3.04-4.75 (m,12H), 7.00 (m, 1H), 7.46 (m, 1H), 7.80-8.18 (m, 5H). APCI MS m/z 491 [M− H]⁻ 48

White solid ¹H NMR (400MHz, CD₃OD): δ196-2.37 (m, 3H), 2.62 (m, 1H),3.36-3.70 (m, 7H), 3.79-3.98 (m, 2H), 4.08 (m, 1H), 4.20-4.66 (m, 4H),5.04-5.62 (m, 2H), 7.02 (dd, 1H), 7.48 (d, 1H), 7.82 (m, 1H), 7.98 (m,2H), 8.06 (m, 1H), 8.18 (m, 1H). APCI MS m/z 494 [MH]⁺ 49

White solid ¹H NMR (400MHz, CD₃OD): δ1.40-2.40 (m, 4H), 3.20-3.78 (m,10H), 3.96-5.41 (m, 6H), 7.00 (m, 1H), 7.41 (d, 1H), 7.74-7.80 (m, 2H),7.95 (d, 1H), 8.02 (m, 1H). APCI MS m/z 516 [MNa]⁺

EXAMPLE 508-Chloro-5-pyrrolidin-(2S)-2-ylmethyl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[0925]

[0926] Borane (1M solution in tetrahydrofuran, 7.25 ml, 7.25 mmol) wasadded to a suspension of the amide from example 43 (398 mg, 0.725 mmol)in tetrahydrofuran (10 ml), and the mixture was heated under reflux for2 hours. Hydrochloric acid (6M) was added until no more gas was evolved,and the reaction mixture was heated under reflux for a further 3 hours.The cooled mixture was basified using 2 N sodium hydroxide solution, andthen extracted with ethyl acetate (×2). The combined organic extractswere washed with brine, dried over magnesium sulphate, and evaporatedunder reduced pressure. The colourless gum was purified by columnchromatography on silica gel using dichloromethane:methanol:0.88 ammonia(80:20:3) as eluant, to afford the title compound as a white foam, 98mg.

[0927]¹H NMR (400 MHz, CDCl₃): δ 1.39 (m, 1H), 1.59-2.18 (m, 7H), 2.58(m, 2H), 2.80-3.76 (m, 10H), 4.23 (m, 2H), 6.50 (dd, 1H), 6.58 (d, 1H),7.22 (d, 1H), 7.36-7.58 (m, 3H), 8.04 (d, 1H).

[0928] APCl MS m/z 464 [MH]⁺

EXAMPLES 51 to 54

[0929] The following compounds of general structure:

[0930] were prepared from the appropriate amides following the proceduredescribed in example 50. Yield (%)/ Ex No R¹ Form Data 51

56 white foam ¹H NMR (400MHz, CDCl₃): δ 1.05-2.23 (m, 10H), 2.40-2.70(m, 3H), 2.96 (m, 2H), 3.12 (m, 2H), 3.27-3.90 (m, 5H), 4.34 (m, 2H),6.58 (dd, 1H), 6.66 (d, 1H), 7.33 (d, 1H), 7.45 (m, 3H), 8.18 (m, 1H).APCI MS m/z 478 [MH]⁺ 52

63 white foam ¹H NMR (400MHz, CDCl₃): δ 1.05-2.05 (m, 10H), 2.40-2.70(m, 3H), 2.97 (m, 2H), 3.10 (m, 2H), 3.10-4.40 (m, 7H), 6.60 (dd, 1H),6.66 (d, 1H), 7.35 (d, 1H), 7.50 (m, 3H), 8.18 (d, 1H). APCI MS m/z 478[MH]⁺ 53

24 white foam ¹H NMR (400MHz, CDCl₃): δ 1.42-2.40 (m, 12H), 2.60 (m,1H), 2.80-3.10 (m, 4H), 3.18-3.65 (m, 5H), 4.22 (m, 2H), 6.50 (dd, 1H),6.59 (d, 1H), 7.18 (s, 1H), 7.21 (d, 1H), 7.39 (m, 2H), 8.06 (m, 1H).APCI MS m/z 478 [MH]⁺ 54

37 white foam ¹H NMR (400MHz, CDCl₃): δ 1.82-2.22 (m, 4H), 2.40-3.00 (m,9H), 3.10 (m, 1H), 3.38-3.90 (m, 6H), 4.36 (m, 2H), 6.60 (dd, 1H), 6.66(d, 1H), 7.33 (d, 1H), 7.42-7.58 (m, 3H), 8.18 (d, 1H). APCI MS m/z 502[MNa]⁺

EXAMPLE 555-Azetidin-3-yl-8-chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[0931]

[0932] Hydrochloric acid in dioxan (5.6 ml, 4M) was added to a solutionof the protected amine from preparation 73 (1.2 g, 2.24 mmol) indichloromethane (10 ml), and the solution was stirred at roomtemperature for 18 hours. The mixture was partitioned between 2N sodiumhydroxide solution and dichloromethane and the layers were separated.The aqueous phase was extracted with dichloromethane (×2) and thecombined organic solutions were washed with brine, dried over magnesiumsulphate, and evaporated under reduced pressure. The residual yellowsolid was purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (95:5:0.5 to 93:7:1) to afford thetitle compound as a white foam (300 mg).

[0933]¹H NMR (400 MHz, CDCl₃): δ 1.60-2.20 (m, 4H), 2.82-3.77 (m, 10H),4.35 (m, 4H), 6.60 (d, 1H), 6.66 (d, 1H), 7.36 (d, 1H), 7.42-7.59 (m,3H), 8.18 (m, 1H).

[0934] APCl MS m/z 458 [MNa]⁺

EXAMPLE 568-Chloro-5-pyrrolidin-3-yl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[0935]

[0936] Hydrochloric acid in dioxan (1.5 ml, 4M) was added to asuspension of the protected amine from preparation 74 (767 mg, 1.39mmol) in dioxan (30 ml) and the reaction mixture was stirred at roomtemperature for 18 hours. TLC analysis showed starting materialremained, so additional hydrochloric acid in dioxan (1.5 ml, 4M) wasadded and the reaction stirred for a further 5 hours. The mixture wasevaporated under reduced pressure and the residue purified by columnchromatography on silica gel using dichloromethane:methanol:0.88 ammonia(90: 10:1). The residue was azeotroped with ether to afford the titlecompound as a brown foam, 404.6 mg.

[0937]¹H NMR (400 MHz, CDCl₃): δ 1.57-2.39 (m, 9H), 2.78-3.57 (m, 9H),4.33 (m, 2H), 6.59 (dd, 1H), 6.66 (d, 1H), 7.32 (d, 1H), 7.44 (m, 1H),7.52 (m, 2H), 8.18 (d, 1H).

[0938] APCl MS m/z 472 [MNa]⁺

EXAMPLE 578-Chloro-5-piperidin-4-yl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulenetrihydrochloride

[0939]

[0940] Hydrochloric acid in dioxan (8.44 ml, 4M) was added to a solutionof the protected amine from preparation 75 (1.9 g, 3.37 mmol) indichloromethane (50 ml), and the reaction mixture was stirred at roomtemperature for 18 hours. The mixture was evaporated under reducedpressure, to give the title compound as a pale pink solid.

[0941]¹H NMR (400 MHz, CD₃OD): δ 1.70-2.35 (m, 6H), 2.55-2.65 (m, 2H),3.03-3.40 (m, 7H), 3.60-3.96 (m, 2H), 4.20-5.08 (m, 4H), 7.01 (dd, 1H),7.43 (d, 1H), 7.90 (s, 2H), 7.98 (dd, 1H), 8.04 (m, 2H).

[0942] APCl MS m/z 464 [MH]⁺

EXAMPLE 588-Chloro-5-[1,4]oxazepan-6-yl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulenetrihydrochloride

[0943]

[0944] Hydrochloric acid in dioxan (1 ml, 4M) was added to a solution ofthe protected amine from preparation 76 (180 mg, 0.31 mmol) in dioxan (5ml), and the reaction mixture was stirred at room temperature for 18hours. The mixture was evaporated under reduced pressure and the residuepurified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant. The productwas dissolved in dichloromethane and the solution treated with etherealhydrochloric acid (1M). The solution was evaporated under reducedpressure to afford the title compound.

[0945]¹H NMR (400 MHz, CD₃OD): δ 2.00-2.60 (m, 4H), 3.36-3.62 (m, 7H),3.70-4.00 (m, 7H), 4.12-4.40 (m, 4H), 7.01 (dd, 1H), 7.43 (d, 1H), 7.78(dd, 1H), 7.81 (m, 1H), 7.90 (s, 1H), 7.98 (d, 1H), 8.05 (m, 1H).

[0946] APCl MS m/z 480 [MH]⁺

EXAMPLE 59 [8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′bipyrdinyl-4-yl)-4H,6H,2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-morpholin-4-yl-methanone

[0947]

[0948] A mixture of the amine from example 4 (150 mg, 0.42 mmol),morpholinecarbonyl chloride (0.15 ml, 1.26 mmol) and triethylamine (0.18ml, 1.26 mmol) in dichloromethane (10 ml) was stirred at roomtemperature for 18 hours. The reaction mixture was evaporated underreduced pressure and the residue purified by column chromatography onsilica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5), toafford the title compound as a white solid (130 mg).

[0949]¹H NMR (400 MHz, CDCl₃): δ 1.56-1.85 (m, 4H), 2.85-3.38 (m, 7H),3.60-3.98 (m, 6H), 4.22-4.54 (m, 3H), 4.78-4.97 (m, 1H), 6.61 (dd, 1H),6.68 (d, 1H), 7.38 (d, 1H), 7.50 (m, 1H), 7.58 (m, 2H), 8.18 (m, 1H).

[0950] APCl MS m/z 516 [MNa]⁺

EXAMPLES 60 to 63

[0951] The following compounds of general structure:

[0952] were prepared from the amine from example 4 and the appropriateacid chlorides following the procedure described in example 59. Yield(%)/ Ex No R¹ Form Data 60

83 white solid ¹H NMR (400MHz, CDCl₃): δ 1.56-2.38 (m, 4H), 2.80-3.18(m, 3H), 3.58-3.98 (m, 5H), 4.18-4.46 (m, 2H), 4.79-5.40 (m, 2H), 6.60(dd, 1H), 6.64 (d, 1H), 7.38 (d, 1H), 7.42 (m, 1H), 7.50-7.61 (m, 2H),8.17 (m, 1H). APCI MS m/z 461 [MNa]⁺ 61^(a)

92 white solid ¹H NMR (400MHz, CDCl₃): δ 1.60-1.95 (m, 2H), 2.05-2.19(m, 2H), 2.83-3.03 (m, 8H), 3.17 (m, 1H), 3.70-4.05 (m, 2H), 4.19-4.55(m, 3H), 4.70-5.94 (m, 1H), 6.62 (m, 1H), 6.69 (d, 1H), 7.38 (d, 1H),7.46 (m, 1H), 7.58 (m, 2H), 8.18 (d, 1H). APCI MS m/z 452 [MH]⁺ 62

93 white foam ¹H NMR (400MHz, CDCl₃): δ 1.58-2.39 (m, 7H), 2.84-3.02 (m,2H), 3.16 (m, 1H), 3.40 (m, 4H), 3.65-4.00 (m, 2H), 4.20-4.62 (m, 4H),4.80-5.02 (m, 1H), 6.60 (dd, 1H), 6.66 (d, 1H), 7.38 (d, 1H), 7.42-7.60(m, 3H), 8.18 (m, 1H). APCI MS m/z 478 [MH]⁺ 63

69 white solid ¹H NMR (400MHz, CDCl₃): δ 1.59-1.95 (m, 3H), 2.18-2.60(m, 7H), 2.82-3.02 (m, 2H), 3.15 (m, 1H), 3.39 (m, 4H), 3.72-4.02 (m,2H), 4.20-4.52 (m, 3H), 4.78-4.96 (m, 1H), 6.60 (dd, 1H), 6.68 (d, 1H),7.38 (d, 1H), 7.45 (dd, 1H), 7.58 (d, 2H), 8.18 (d, 1H). APCI MS m/z 507[MH]⁺

EXAMPLE 64{2-[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-ethyl}-dimethyl-aminetrihydrochloride

[0953]

[0954] Borane (1M solution in tetrahydrofuran, 4.3 ml, 4.3 mmol) wasadded to a suspension of the amide from example 61 (398 mg, 0.43 mmol)in tetrahydrofuran (10 ml) and the was mixture heated under reflux for 2hours. Hydrochloric acid (6M) was added until no more gas was evolved,and the reaction was then heated under reflux for a further 3 hours. Thecooled mixture was basified using 2 N sodium hydroxide solution, andthen extracted with dichloromethane (3×20 ml). The combined organicextracts were washed with brine (20 ml), dried over magnesium sulphate,and evaporated under reduced pressure. The colourless gum was purifiedby column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (93:7:1) as eluant, to afford acolourless gum. This gum was treated with ethereal hydrochloric acid toafford the title compound (194 mg).

[0955]¹H NMR (400 MHz, CD₃OD): δ 2.00-2.19 (m, 4H), 3.00 (m, 6H), 3.18(m, 2H), 3.42-4.46 (m, 11H), 7.00 (dd, 1H), 7.42 (d, 1H), 7.79 (dd, 1H),7.63 (m, 2H), 7.97 (m, 1H), 8.03 (m, 1H).

[0956] APCl MS m/z 452 [MH]⁺

EXAMPLE 658-Chloro-5-(2-pyrrolidin-1-yl-ethyl)-l-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulenetrihydrochloride

[0957]

[0958] The title compound was obtained in 15% yield from the amide fromexample 62, following a similar procedure to that described in example64.

[0959]¹H NMR (400 MHz, CD₃OD): δ 2.03-2.23 (m, 8H), 3.00-3.83 (m, 13H),4.00-4.80 (m, 4H), 7.00 (m, 1H), 7.43 (d, 1H), 7.80-8.08 (m, 5H).

[0960] APCl MS m/z 478 [MH]⁺

EXAMPLE 66[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-aceticacid methyl ester

[0961]

[0962] A mixture of the amine from example 4 (500 mg, 1.31 mmol), methylbromoacetate (260 mg, 1.70 mmol) and potassium carbonate (220 mg, 1.59mmol) in N,N-dimethylformamide (15 ml) was stirred at room temperaturefor 72 hours. The mixture was evaporated under reduced pressure and theresidue purified directly by column chromatography on silica gel usingdichloromethane:methanol (93:7) as eluant to afford the title compound.

[0963]¹H NMR (400 MHz, CDCl₃): δ 1.42-2.40 (m, 4H), 3.00-3.22 (m, 3H),3.39-3.98 (m, 9H), 4.38 (m, 2H), 6.63 (m, 1H), 6.74 (m, 1H), 7.36 (d,1H), 7.57 (m, 3H), 8.18 (d, 1H).

[0964] APCl MS m/z 453 [MH]⁺

EXAMPLE 671-[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-3-methoxy-propan-1-one

[0965]

[0966] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (116mg, 0.6 mmol) followed by 1-hydroxybenzotriazole hydrate (81 mg, 0.6mmol) and triethylamine (84 μl, 0.6 mmol) were added to a solution of3-methoxypropionic acid (63 mg, 0.6 mmol) in dichloromethane (10 ml) andthe solution stirred for 10 minutes. The amine from example 4 (150 mg,0.4 mmol) was added and the reaction stirred at room temperature for 5hours. The reaction was washed with saturated sodium bicarbonatesolution, dried over magnesium sulphate and evaporated under reducedpressure. The residue was purified by column chromatography on silicagel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) to give thetitle compound as a white solid, 166 mg.

[0967]¹H NMR (400 MHz, CDCl₃): δ 1.57-2.38 (m, 4H), 2.63-3.03 (m, 4H),3.14 (m, 1H), 3.26 (s, 3H), 3.78-3.98 (m, 3H), 4.23-4.43 (m, 3H),4.75-4.92 (m, 1H), 5.44-5.62 (m, 1H), 6.61 (dd, 1H), 6.68 (d, 1H), 7.40(dd, 1H), 7.46 (m, 1H), 7.58 (m, 2H), 8.18 (d, 1H).

[0968] APCl MS m/z 489 [MNa]⁺

EXAMPLE 681-[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-3-dimethylamino-propan-1-one

[0969]

[0970] O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (200 mg, 0.52 mmol) was added to a solution of3-dimethylaminopropionic acid hydrochloride (80 mg, 0.52 mmol) indichloromethane (5 ml) and the solution was stirred for 15 minutes. Theamine from example 4 (100 mg, 0.26 mmol) was added and the reactionmixture was stirred at room temperature for 18 hours. The mixture waspartitioned between dichloromethane and aqueous sodium bicarbonatesolution, and the layers were separated. The organic phase was driedover magnesium sulphate and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (90:10:1), to afford the titlecompound as a white solid (110 mg).

[0971]¹H NMR (400 MHz, CDCl₃): δ 1.60-2.00 (m, 2H), 2.20 (m, 3H), 2.38,2.42 (2xs, 6H), 2.62 (m, 1H), 2.75-3.00 (m, 4H), 3.14 (m, 1H), 3.97-4.80(m, 4H), 5.05-5.66 (m, 2H), 6.60 (dd, 1H), 6.66 (d, 1H), 7.40 (m, 1H),7.46 (m, 1H), 7.59 (m, 2H), 8.18 (d, 1H).

[0972] APCl MS m/z 480 [MH]⁺

EXAMPLE 698-Chloro-5-(1-methyl-pyrrolidin-(2S)-2-ylmethyl)-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulenetrihydrochloride

[0973]

[0974] Formaldehyde (0.1 ml, 33 wt. % solution in water) and sodiumtriacetoxyborohydride (64 mg, 0.30 mmol) were added to a suspension ofthe amine from example 50 (70 mg, 0.15 mmol) in dichloromethane (5 ml)and the reaction mixture was stirred at room temperature for 2 hours.The mixture was partitioned between dichloromethane and 2 N sodiumhydroxide solution and the phases separated. The organic solution wasevaporated under reduced pressure and the residue purified by columnchromatography on silica gel using dichloromethane:methanol:0.88 ammonia(93:7:1) as eluant. The product was treated with ethereal hydrochloricacid, and the solution evaporated under reduced pressure to give thetitle compound (35 mg).

[0975]¹H NMR (400 MHz, CD₃OD): δ 1.78-2.98 (m, 9H), 2.96-3.38 (m, 8H),3.40-4.38 (m, 8H), 7.01 (dd, 1H), 7.43 (d, 1H), 7.80 (m, 1H), 7.89 (m,2H), 7.98 (d, 1H), 8.06 (dd, 1H).

[0976] APCl MS m/z 502 [MH]⁺

EXAMPLES 70 to 72

[0977] The following compounds of general structure:

[0978] were prepared from the appropriate amines and formaldehydefollowing a similar procedure to that described in example 69, Yield(%)/ Ex No R¹ Form Data 70^(a)

67 white foam ¹H NMR (400MHz, CDCl₃): δ 1.26 (m, 2H), 1.57 (m, 2H),1.70-2.47 (m, 10H), 2.80 (m, 2H), 3.96 (m, 2H), 3.12 (m, 1H), 3.27-3.80(m, 6H), 4.36 (m, 2H), 6.58 (dd, 1H), 6.62 (d, 1H), 7.31 (d, 1H), 7.44(m, 3H), 8.18 (m, 1H). APCI MS m/z 492 [MH]⁺ 71^(a)

70 white foam ¹H NMR (400MHz, CDCl₃): δ 1.26 (m, 2H), 1.58 (m, 2H),1.70-2.45 (m, 10H), 2.79-3.00 (m, 4H), 3.12 (m, 1H), 3.24-3.81 (m, 6H),4.36 (m, 2H), 6.59 (dd, 1H), 6.62 (d, 1H), 7.31 (d, 1H), 7.41-7.56 (m,3H), 8.18 (m, 1H). APCI MS m/z 492 [MH]⁺ 72

57 white foam ¹H NMR (400MHz, CD₃OD): δ 1.83-2.62 (m, 8H), 2.81-3.02 (m,6H), 3.22-3.97 (m, 7H), 4.02-4.98 (m, 6H), 7.00 (dd, 1H), 7.45 (d, 1H),7.90 (s, 2H), 7.98 (d, 1H), 8.02 (m, 2H). APCI MS m/z 492 [MH]⁺

EXAMPLE 73 and 74 (+) and (−)8-Chloro-5-(4-methyl-morpholin-2-ylmethyl)-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[0979]

[0980] Formaldehyde (0.1 ml, 37 wt. % solution in water) and sodiumtriacetoxyborohydride (55 mg, 0.26 mmol) were added to a suspension ofthe amine from example 54 (60 mg, 0.12 mmol) in dichloromethane (5 ml)and the reaction mixture was stirred at room temperature for 2 hours.The mixture was partitioned between dichloromethane and 2 N sodiumhydroxide solution and the phases separated. The organic solution wasevaporated under reduced pressure and the residue purified by columnchromatography on silica gel using dichloromethane:methanol:0.88 ammonia(93:7:1) as eluant. The product was then purified by HPLC using aChiralcel OD 250×20 mm column, and methanol as eluant to afford thetitle compound of example 73;

[0981]¹H NMR (400 MHz, CDCl₃): δ 1.60-2.30 (m, 9H), 2.55-2.81 (m, 4H),2.96 (m, 2H), 3.13 (m, 1H), 3.38-3.98 (m, 7H), 4.37 (m, 2H), 6.60 (dd,1H), 6.66 (d, 1H), 7.32 (d, 1H), 7.42-7.59 (m, 3H), 8.18 (m, 1H).⁻

[0982] APCl MS m/z 516 [MNa]⁺

[0983] [α]_(D)=−1.20 (c=0.33, methanol) and the title compound ofexample 74.

[0984]¹H NMR (400 MHz, CDCl₃): δ 1.60-2.20 (m, 6H), 2.30 (s, 3H),2.50-2.79 (m, 4H), 2.96 (m, 2H), 3.13 (m, 1H), 3.20-3.79 (m, 6H), 3.92(m, 1H), 4.37 (m, 2H), 6.60 (dd, 1H), 6.65 (d, 1H), 7.32 (d, 1H),7.42-7.59 (m, 3H), 8.18 (m, 1H).

[0985] APCl MS m/z 516 [MNa]⁺

[0986] [α]_(D)=+3.43 (c=0.23, methanol)

EXAMPLE 75 [8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-((2S)-1-methyl-pyrrolidin-2-yl)-methanone

[0987]

[0988] Formaldehyde (37 wt. % in water, 0.1 ml), triethylamine (0.5 ml),acetic acid (0.5 ml) and sodium triacetoxyborohydride (135 mg, 0.63mmol) were added to a suspension of the amine from example 43 (175 mg,0.32 mmol) in dichloromethane (10 ml) and the reaction mixture wasstirred at room temperature for 1 hour. The mixture was partitionedbetween dichloromethane (50 ml) and 2 N sodium hydroxide solution (50ml), and the phases were separated. The organic solution was evaporatedunder reduced pressure and the residue purified by column chromatographyon silica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) aseluant, to afford the title compound as a white foam (103 mg).

[0989]¹H NMR (400 MHz, CDCl₃): δ 1.60-2.04 (m, 6H), 2.20-2.52 (m, 5H),2.84-3.23 (m, 6H), 3.60-4.46 (m, 4H), 5.50-5.85 (m, 2H), 6.60 (dd, 1H),6.66 (d, 1H), 7.38-7.48 (m, 2H), 7.58-7.63 (m, 2H), 8.18 (m, 1H).

[0990] APCl MS m/z 492 [MH]⁺

EXAMPLES 76 to 81

[0991] The following compounds of general structure:

[0992] were prepared from the appropriate amines and formaldehydefollowing a similar procedure to that described in example 75. Yield(%)/ Ex No R¹ Foam Data 76

57 white foam ¹H NMR (400MHz, CDCl₃): δ 1.56-2.40 (m, 11H), 2.83-3.28(m, 6H), 3.61-3.91 (m, 2H), 4.23-4.42 (m, 2H), 5.46-5.86 (m, 2H), 6.60(dd, 1H), 6.66 (d, 1H), 7.37-7.50 (m, 2H), 7.57-7.63 (m, 2H), 8.18 (d,1H). APCI MS m/z 492 [MH]⁺Microanalysis found: C, 61.34; H, 6.23; N,18.93. C₂₆H₃₀ClN₇O; 0.25CH₂Cl₂ requires C, # 61.43; H, 5.99; N, 19.10%.77^(a)

29 ¹H NMR (400MHz, CDCl₃): δ 1.58-1.97 (m, 2H), 2.03-2.38 (m, 4H),2.38-2.60 (m, 4H), 2.70-3.19 (m, 4H), 3.20-3.45 (m, 1H), 3.63-4.98 (m,6H), 5.00-5.62 (m, 2H), 6.60 (dd, 1H), 6.66 (d, 1H), 7.38-7.56 (m, 2H),7.59 (m, 2H), 8.18 (m, 1H). APCI MS m/z 492 [MH]⁺ 77^(b)

¹H NMR (400MHz, CD₃OD): δ1.64-2.02 (m, 8H), 2.25 (m, 2H), 2.58 (m, 1H),2.85 (m, 4H), 3.18-3.60 (m, 3H), 3.80 (m, 1H), 3.98-4.70 (m, 4H),4.82-5.78 (m, 2H), 7.01 (m, 1H), 7.43 (d, 1H), 7.80-7.95 (m, 3H), 7.98(d, 1H), 8.04 (m, 1H), 8.20 (br s, 1H). APCI MS m/z 506 [MH]⁺ 79

59 ¹H NMR (400MHz, CDCl₃): δ 1.42-2.38 (m, 11H), 2.61 (m, 1H), 2.77-3.18(m, 5H), 3.14-4.82 (m, 6H), 5.18-5.60 (m, 2H), 6.60 (dd, 1H), 6.60 (d,1H), 7.38-7.52 (m, 2H), 7.58 (m, 2H), 8.18 (d, 1H). APCI MS m/z 506[MH]⁺ 80

54 ¹H NMR (400MHz, CDCl₃): δ 1.58-2.42 (m, 7H), 2.61-2.76 (m, 1H),2.81-3.19 (m, 5H), 3.44-4.52 (m, 8H), 4.99-5.60 (m, 2H), 6.60 (dd, 1H),6.60 (d, 1H), 7.39 (dd, 1H), 7.45 (dd, 1H), 7.58 (m, 2H), 8.18 (m, 1H).APCI MS m/z 508 [MH]⁺ 81^(a)

62 ¹H NMR (400MHz, CDCl₃): δ 1.62-2.42 (m, 8H), 2.79-3.20 (m, 4H), 3.35(m, 1H), 3.59-3.97 (m, 6H), 4.20-4.42 (m, 2H), 5.00-5.70 (m, 2H), 6.59(dd, 1H), 6.63 (d, 1H), 7.36-7.45 (m, 2H), 7.58 (m, 2H), 8.16 (m, 1H).APCI MS m/z 508 [MH]⁺

EXAMPLE 828-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-(tetrahydro-pyran-4-yl)-methanone

[0993]

[0994] O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (243 mg, 0.64 mmol) was added to a solution oftetrahydro-4-pyrancarboxylic acid (J. Med. Chem. 37 (26), 4549, 1994)(82 mg, 0.64 mmol) in dichloromethane (10 ml) and the solution wasstirred for 30 minutes. The amine from example 4 (120 mg, 0.32 mmol) wasadded and the reaction mixture was stirred at room temperature for 18hours. TLC analysis showed that starting material remained, soadditional O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (122 mg, 0.32 mmol) and tetrahydro-4-pyrancarboxylicacid (41 mg, 0.32 mmol) were added, and the reaction mixture was stirredfor a further 24 hours. The mixture was partitioned betweendichloromethane and aqueous saturated sodium bicarbonate solution, andthe layers separated. The organic phase was dried over magnesiumsulphate and evaporated under reduced pressure. The crude product waspurified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant, to affordthe title compound as a white solid (105 mg).

[0995]¹H NMR (400 MHz, CDCl₃): δ 1.58-2.42 (m, 10H), 2.81 (m, 1H),2.98-3.22 (m, 4H), 3.50 (m, 2H), 3.97-4.17 (m, 2H), 4.22-4.50 (m, 2H),5.08-5.46 (m, 1H), 6.60-6.78 (m, 2H), 7.40 (d, 1H), 7.50-7.65 (m, 3H),8.20 (d, 1H).

[0996] APCl MS m/z 493 [MH]⁺

EXAMPLE 83[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-(1-methyl-piperidin-4-yl)-methanone

[0997]

[0998] O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (395 mg, 1.04 mmol) was added to a solution of1-methylpiperidine-4-carboxylic acid hydrochloride (210 mg, 1.04 mmol)in dichloromethane (10 ml) and the solution stirred for 30 minutes. Theamine from example 4 (200 mg, 0.52 mmol) was added and the reactionmixture was stirred at room temperature for 18 hours. The mixture waswashed with aqueous sodium carbonate solution and the organic solutionwas dried over magnesium sulphate. The solution was evaporated underreduced pressure and the crude product was purified by columnchromatography on silica gel using ethyl acetate:methanol:0.88 ammonia(90:10:1) as eluant, to afford the title compound as a white solid (195mg).

[0999] APCl MS m/z 506 [MH]⁺

EXAMPLE 848-Chloro-5-(1-methyl-azetidin-3-yl)-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[1000]

[1001] Formaldehyde (37% in water, 0.1 ml), triethylamine (0.5 ml),acetic acid (0.5 ml) and sodium triacetoxyborohydride (75 mg, 0.36 mmol)were added to a suspension of the amine from example 55 (77 mg, 0.18mmol) in dichloromethane (10 ml), and the reaction mixture was stirredat room temperature for 3 hours. The mixture was partitioned betweendichloromethane and 2 N sodium hydroxide solution, and the phases wereseparated. The aqueous layer was extracted with further dichloromethaneand the combined organic solutions evaporated under reduced pressure.The residue was purified by column chromatography on silica gel usingdichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant, to affordthe title compound as a white foam (72 mg).

[1002]¹H NMR (400 MHz, CDCl₃): δ 1.79-2.21 (m, 4H), 2.40 (s, 3H),2.83-3.78 (m, 12H), 4.34 (m, 2H), 6.60 (dd, 1H), 6.66 (d, 1H), 7.34 (d,1H), 7.42-7.58 (m, 3H), 8.18 (d, 1H).

[1003] APCl MS m/z 450 [MH]⁺

EXAMPLES 85 to 88

[1004] The following compounds of general structure:

[1005] were prepared from the appropriate amines and aldehydes orketones following a similar procedure to that described in example 84.Yield (%)/ Ex No R¹ Form Data 85

62 white foam ¹H NMR (400MHz, CDCl₃): δ 0.95 (d, 6H), 1.78-2.40 (m, 5H),2.86-3.60 (m, 12H), 4.36 (m, 2H), 6.60 (dd, 1H), 6.65 (d, 1H), 7.34 (d,1H), 7.44 (m, 2H), 7.53 (d, 1H), 8.18 (d, 1H). APCI MS m/z 478 [MH]⁺ 86

29 ¹H NMR (400MHz, CDCl₃): δ 1.60-2.08 (m, 8H), 2.25 (s, 3H), 2.51 (m,1H), 2.80-3.01 (m, 4H), 3.17 (m, 1H), 3.40-3.96 (m, 6H), 4.36 (m, 2H),6.60 (m, 1H), 6.66 (d, 1H), 7.30 (d, 1H), 7.41-7.58 (m, 3H), 8.18 (d,1H). APCI MS m/z 478 [MH]⁺ 87

32 ¹H NMR (400MHz, CDCl₃): δ 1.10 (t, 3H), 1.54-2.10 (m, 8H), 2.40 (q,2H), 2.54 (m, 1H), 2.76-3.03 (m, 6H), 3.17 (m, 1H), 3.42-4.96 (m, 4H),4.36 (m, 2H), 6.60 (m, 1H), 6.66 (d, 1H), 7.30 (d, 1H), 7.41-7.58 (m,3H), 8.18 (d, 1H). APCI MS m/z 492 [MH]⁺ 88

30 ¹H NMR (400MHz, CDCl₃): δ 1.10 (d, 6H), 1.72-2.38 (m, 8H), 2.58 (m,1H), 2.78-3.03 (m, 7H), 3.14 (m, 1H), 3.38-4.00 (m, 4H), 4.36 (m, 2H),6.60 (m, 1H), 6.66 (d, 1H), 7.30 (d, 1H), 7.41-7.58 (m, 3H), 8.18 (d,1H). APCI MS m/z 528 [MNa]⁺

EXAMPLE 898-Chloro-5-(1-methyl-pyrrolidin-3-yl)-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[1006]

[1007] Formaldehyde (18 μl, 37 wt. % solution in water, 0.22 mmol) andsodium triacetoxyborohydride (47 mg, 0.22 mmol) were added to a solutionof the amine from example 56 (100 mg, 0.22 mmol) in dichloromethane (5ml), and the reaction mixture was stirred at room temperature for 30minutes. Saturated aqueous sodium bicarbonate solution (10 ml) wasadded, the mixture was stirred vigorously for 10 minutes, and the layerswere separated. The organic layer was evaporated under reduced pressureand the residue purified by column chromatography on silica gel usingdichloromethane:methanol: 0.88 ammonia (95:5:0.5) as eluant. The productwas azeotroped with ether to afford the title compound (60 mg).

[1008]¹H NMR (400 MHz, CDCl₃): δ 1.74-2.30 (m, 8H), 2.34 (s, 3H), 2.45(s, 1H), 2.57 (d, 1H), 2.66 (d, 1H), 2.80 (t, 1H), 2.93 (s, 2H), 3.12(t, 1H), 3.23 (t, 1H), 3.48 (s, 2H), 4.33 (s, 2H), 6.60 (t, 1H), 6.64(d, 1H), 7.32 (d, 1H), 7.45 (t, 1H), 7.52 (m, 2H), 8.15 (d, 1H).

[1009] APCl MS m/z 564 [MH]⁺

EXAMPLE 908-Chloro-5-(1-isopropyl-pyrrolidin-3-yl)-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulenetrihydrochloride

[1010]

[1011] Acetone (0.1 ml) and sodium triacetoxyborohydride (47 mg, 0.22mmol) were added to a solution of the amine from example 56 (100 mg,0.22 mmol) in dichloromethane (5 ml), and the reaction mixture wasstirred at room temperature for 16 hours. Saturated aqueous sodiumbicarbonate solution (10 ml) was added, the mixture was stirredvigorously for 10 minutes, and the layers were separated. The organiclayer was evaporated under reduced pressure and the residue purified bycolumn chromatography on silica gel using dichloromethane:methanol:0.88ammonia (95:5:0.5) as eluant. The product was treated with etherealhydrochloric acid to afford the title compound.

[1012]¹H NMR (400 MHz, CD₃OD): δ 1.43 (d, 6H), 1.85-2.70 (m, 4H),3.35-4.85 (m, 17H), 7.02 (t, 1H), 7.47 (d, 1H), 7.80-7.92 (m, 2H), 7.97(d, 2H), 8.06 (t, 1H).

[1013] APCl m/z 492 [MH]⁺

EXAMPLE 91 2-[8-Chloro-1-(1-pyrimidin-2-yl-piperidin-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-ethanol

[1014]

[1015] N,N-Diisopropylethylamine (80 μl, 0.62 mmol), followed by2-chloroethanol (52 μl, 0.78 mmol) were added to a solution of the aminefrom example 12 (200 mg, 0.52 mmol) in N,N-dimethylformamide (6 ml), andthe reaction mixture was stirred at room temperature for 18 hours. Themixture was concentrated under reduced pressure and the residue waspurified by column chromatography on silica gel using ethylacetate:methanol:0.88 ammonia (90:10:1) as eluant, to give the titlecompound as an off-white solid (120 mg).

[1016]¹H NMR (400 MHz, CDCl₃): δ 1.62-2.22 (m, 3H), 2.62 (m, 1H), 2.84(m, 2H), 3.00 (m, 2H), 3.18 (m, 1H), 3.38-3.90 (m, 6H), 4.80 (m, 2H),6.46 (m, 1H), 7.38 (d, 1H), 7.58 (m, 2H), 8.30 (s, 2H).

[1017] APCl MS m/z 426 [MH]⁺

EXAMPLE 928-Chloro-5-(2-methoxy-ethyl)-1-(1-pyrimidin-2-yl-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[1018]

[1019] N,N-Diisopropylethylamine (80 μl, 0.62 mmol), followed by2-bromomethoxyethane (0.2 ml, 0.62 mmol) were added to a solution of theamine from example 12 (200 mg, 0.52 mmol) in N,N-dimethylformamide (6ml) and the reaction mixture was stirred at 80° C. for 18 hours. Themixture was concentrated under reduced pressure and the residue purifiedby column chromatography on silica gel using ethyl acetate:methanol:0.88ammonia (95:5:0.5) to give the title compound as a gum (76 mg).

[1020]¹H NMR (400 MHz, CDCl₃): δ 1.84-2.16 (m, 4H), 2.78-3.20 (m, 5H),3.20-4.50 (m, 9H), 4.80 (m, 2H), 6.48 (dd, 1H), 7.32 (d, 1H), 7.58 (m,2H), 8.30 (d, 2H).

[1021] APCl MS m/z 462 [MNa]⁺

EXAMPLE 938-Chloro-5-pyrimidin-2-yl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[1022]

[1023] A mixture of the amine from example 4 (200 mg, 0.53 mmol),2-chloropyrimidine (66 mg, 0.58 mmol) and potassium carbonate (72 mg,0.53 mmol) in N,N-dimethylformamide (5 ml) was stirred at roomtemperature for 18 hours. TLC analysis showed starting materialsremained, so additional 2-chloropyrimidine (66 mg, 0.58 mmol) was added,and the reaction was stirred at 80° C. for a further 72 hours. Thecooled mixture was evaporated under reduced pressure, the residue waspartitioned between ethyl acetate and brine, and the layers wereseparated. The organic layer was washed with water, wash with ammoniumchloride solution, dried over magnesium sulphate and then evaporatedunder reduced pressure. The residual yellow oil was purified by columnchromatography on silica gel using dichloromethane:methanol (95:5) aseluant, to afford the title compound as a yellow oil (117 mg).

[1024]¹H NMR (400 MHz, CDCl₃): δ 1.61-2.40 (m, 4H), 2.82-3.19 (m, 3H),3.63-4.48 (m, 4H), 5.60-5.84 (m, 2H), 6.60 (m, 2H), 6.66 (d, 1H), 7.40(d, 1H), 7.43 (m, 1H), 7.52 (m, 1H), 7.60 (s, 1H), 8.16 (m, 1H), 8.38(d, 2H).

[1025] APCl m/z 459 [MH]⁺

EXAMPLE 948-Chloro-5-pyrimidin-4-yl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[1026]

[1027] A mixture of the amine from example 4 (500 mg, 1.3 mmol),potassium carbonate (480 mg, 3.5 mmol) and 4-chloropyrimidine (300 mg,2.6 mmol) was stirred at 95° C. for 18 hours. The cooled reactionmixture was diluted with ethyl acetate and the solution was washed withbrine (5×), then dried over magnesium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography on silica gel using dichloromethane:methanol (100:0 to95:5) as eluant, and the product was triturated with diethyl ether toafford the title compound (80 mg).

[1028]¹H NMR (400 MHz, CDCl₃): δ 1.80-2.24 (m, 4H), 2.97 (m, 2H), 3.18(m, 1H), 3.90-4.43 (m, 4H), 5.20-5.80 (m, 2H), 6.56 (d, 1H), 6.60 (m,1H), 6.66 (d, 1H), 7.42 (m, 2H), 7.57 (d, 1H), 7.62 (s, 1H), 8.18 (m,1H), 8.32 (d, 1H), 8.70 (s, 1H).

[1029] APCl m/z 459 [MH]⁺

EXAMPLE 958-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carbaldehyde

[1030]

[1031] A solution of the amine from example 4 (300 mg, 0.79 mmol) informic acid (15 ml) was stirred at 80° C. for 3 hours. The cooledmixture was concentrated under reduced pressure and the residue waspartitioned between ethyl acetate and sodium bicarbonate solution. Thelayers were separated, and the organic phase was evaporated underreduced pressure to give the title compound.

[1032]¹H NMR (400 MHz, CDCl₃): δ 1.60-2.42 (m, 4H), 2.98-3.24 (m, 3H),3.78-4.58 (m, 5H), 5.43 (m, 1H), 6.62 (m, 1H), 6.75 (m, 1H), 7.40 (m,1H), 7.55 (m, 1H), 7.60 (d, 1H), 8.18 (m, 1H), 8.21 (d, 1H).

[1033] APCl m/z 409 [MH]⁺

EXAMPLE 968-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-sulphonicacid dimethylamide

[1034]

[1035] Dimethylsulphamoyl chloride (0.12 ml, 1.08 mmol) was added to asolution of the amine from example 4 (140 mg, 0.36 mmol) and pyridine(90 μl, 1.08 mmol) in dichloromethane (8 ml), and the reaction mixturewas stirred at room temperature for 18 hours. TLC analysis showed thatstarting material remained, so additional dimethylsulphamoyl chloride(0.08 ml, 0.72 mmol) was added and the mixture was stirred for a further24 hours. The mixture as washed with saturated aqueous sodiumbicarbonate solution, dried over magnesium sulphate, and evaporatedunder reduced pressure. The crude product was purified by columnchromatography on silica gel using dichloromethane:methanol:0.88 ammonia(95:5:0.5) as eluant, to afford the title compound as a pale yellow gum(120 mg).

[1036]¹H NMR (400 MHz, CDCl₃): 81.58-1.94 (m, 2H), 2.10-2.40 (m, 2H),2.78-3.02 (m, 8H), 3.15 (m, 1H), 3.62-4.00 (m, 2H), 4.21-4.97 (m, 4H),6.60 (dd, 1H), 6.67 (d, 1H), 7.39 (d, 1H), 7.47 (dd, 1H), 7.59 (d, 1H),7.62 (s, 1H), 8.19 (d, 1H).

[1037] APCl MS m/z 488 [MH]⁺

EXAMPLE 978-Chloro-5-pyridin-2-ylmethyl-1-(1-pyrimidin-2-yl-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[1038]

[1039] Sodium triacetoxyborohydride (277 mg, 1.31 mmol) was added to amixture of the amine from example 12 (250 mg, 0.65 mmol), 2-pyridinecarboxaldehyde (105 mg, 0.98 mmol), and acetic acid (3 drops) indichloromethane (5 ml), cooled to 5° C., and the reaction mixture wasthen stirred at room temperature for 18 hours. 0.88 Ammonia was added tothe reaction mixture, the phases were separated and the organic layerwas dried over magnesium sulphate and evaporated under reduced pressure.The crude product was purified by column chromatography on silica gelusing dichloromethane:methanol (95:5) as eluant, to afford the titlecompound (167 mg)

[1040]¹H NMR (400 MHz, CDCl₃): δ 1.78-2.26 (m, 4H), 3.00, 3.18 (2xm,4H), 3.35-3.60, 3.80-3.98 (2xm, 5H), 4.80 (m, 2H), 6.48 (dd, 1H), 7.22(m, 1H), 7.37 (d, 1H), 7.53 (m, 3H), 7.75 (m, 1H), 8.30 (s, 2H), 8.60(d, 1H).

[1041] APCl MS m/z 473 [MH]⁺

EXAMPLES 98 to 99

[1042] The following compounds of general structure:

[1043] were prepared from the appropriate amines following a similarprocedure to that described in example 97. Ex No R Data 98

¹H NMR (400MHz, CDCl₃): δ 1.79-2.12 (m, 4H), 3.00 (m, 2H), 3.18 (m, 1H),3.26-3.64 (m, 3H), 4.06 (m, 3H), 4.65-5.00 (m, 3H), 6.45 (s, 1H), 7.35(m, 3H), 7.50 (s, 1H), 7.58 (d, 1H), 8.28 (d, 2H). APCI MS m/z 479 [MH]⁺99

¹H NMR (400MHz, CDCl₃): δ 1.75-2.25 (m, 4H), 2.99 (m, 2H), 3.18 (m, 1H),3.20-4.06 (m, 6H), 4.79 (m, 2H), 6.33 (s, 1H), 6.45 (m, 1H), 7.35 (d,1H), 7.52 (m, 3H), 8.26 (m, 2H). APCI MS m/z 462 [MH]⁺

EXAMPLE 1008-Chloro-1-(1-pyrimidin-2-yl-piperidin-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-sulphonicacid dimethylamide

[1044]

[1045] N,N-Diisopropylethylamine (77 μl, 0.44 mmol), followed bydimethylsulphamoyl chloride (50 μl, 0.44 mmol) were added to an ice-coldsolution of the amine from example 12 (150 mg, 0.4 mmol) indichloromethane (10 ml), and the reaction mixture was stirred at roomtemperature for 4 hours. TLC analysis showed that starting materialremained, so additional dimethylsulphamoyl chloride (91 μl, 0.8 mmol)and N,N-diisopropylethylamine (140 μl, 0.8 mmol) were added, and themixture was stirred at room temperature for a further 18 hours. Themixture was evaporated under reduced pressure, the residue waspartitioned between dichloromethane and aqueous sodium bicarbonatesolution, the layers were separated, and the organic phase wasevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel using dichloromethane:methanol:0.88ammonia (95:5:0.5) as eluant, to afford the title compound as anoff-white solid (135 mg).

[1046]¹H NMR (400 MHz, CDCl₃): δ 1.58-1.89 (m, 2H), 2.16-2.35 (m, 2H),2.83-3.19 (m, 9H), 3.63-3.99 (m, 2H), 4.59-4.97 (m, 4H), 6.50 (dd, 1H),7.38 (d, 1H), 7.59 (d, 1H), 7.63 (s, 1H), 8.30 (d, 2H).

[1047] APCl MS m/z 489 [MH]⁺

EXAMPLE 1018-Chloro-5-methyl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4,5-dihydro-2,3,5,10b-tetraaza-benzo[e]azulen-6-one

[1048]

[1049] Acetic acid (2 drops) was added to a solution of the amine frompreparation 62 (250 mg, 0.59 mmol) in toluene (6 ml), and the reactionmixture was stirred under reflux for 3 hours. The cooled mixture waspurified directly by column chromatography on silica gel using ethylacetate:dichloromethane:methanol (100:0:0 to 0:95:5) as eluant. Theproduct was azeotroped with dichloromethane (2×10 ml) and ether (4×10ml) to give the title compound as a white foam (151 mg).

[1050]¹H NMR (400 MHz, DMSOd₆): δ 1.45 (m, 2H), 1.92 (m, 2H), 2.74 (m,1H), 2.85-3.35 (m, 5H), 4.10 (m, 1H), 4.32-4.60 (m, 3H), 6.51 (m, 1H),6.74 (d, 1H), 7.42 (m, 1H), 7.61-7.84 (m, 3H), 8.00 (s, 1H).

[1051] APCl m/z 409 [MH]⁺

EXAMPLE 10213-Chloro-9-methyl-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-2,4,5,9-tetraaza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),3,5,12,14-pentaene

[1052]

[1053] A mixture of the compound from preparation 80 (140 mg, 0.55 mmol)and the hydrazide from preparation 1 (121 mg, 0.55 mmol) in ethanol (2ml) was heated under reflux for 23 hours, then allowed to cool. Themixture was concentrated under reduced pressure and the residue waspurified by column chromatography on silica gel using an elutiongradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1).The product was dissolved in dichloromethane (6 ml) and the solution wastreated with polymer bound isocyanate (0.6 g, 1.5 mmol/g), and themixture was stirred for 1 hour. The mixture was filtered and thefiltrate was evaporated under reduced pressure, to afford the titlecompound (57 mg).

[1054]¹H NMR (400 MHz, CDCl₃): δ 1.42 (m, 1H), 1.63 (m, 1H), 2.18 (m,1H), 2.30 (m, 2H), 2.42 (s, 3H), 2.78 (m, 2H), 2.83-3.05 (m, 3H), 3.18(m, 2H), 3.61 (d, 1H), 4.18 (m, 1H), 4.39 (m, 1H), 6.58 (m, 1H), 6.62(d, 1H), 7.19 (d, 1H), 7.42 (m, 2H), 7.52 (s, 1H), 8.14 (m, 1H).

[1055] APCl MS m/z 409 [MH]⁺

EXAMPLE 10313-Chloro-8-methyl-3-(1-pyrimidin-2-yl-piperidin-4-yl)-2,4,5,8-tetraaza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),3,5,12,14-pentaene

[1056]

[1057] Trifluoroacetic acid (1.5 ml) was added to a solution of thecompound from preparation 63 (1.60 g, 3.72 mmol) in toluene (100 ml),and the mixture was stirred at 60° C. for 24 hours. The cooled mixturewas concentrated under reduced pressure and the residue was partitionedbetween dichloromethane and sodium bicarbonate solution. The layers wereseparated, the organic phase was dried over magnesium sulphate, andevaporated under reduced pressure. The residual oil was purified bycolumn chromatography on silica gel using dichloromethane:methanol(95:5) as eluant. The product was suspended in dichloromethane (100 ml),and treated with activated carbon. The mixture was filtered, thefiltrate was evaporated under reduced pressure, and the residue waspurified by column chromatography on silica gel usingdichloromethane:methanol (96:4) as eluant, to afford the title compoundas an oil (469 mg).

[1058]¹H NMR (400 MHz, CDCl₃): δ 1.42 (m, 1H), 1.62 (m, 1H), 2.18 (m,1H), 2.25 (m, 2H), 2.42 (s, 3H), 2.60 (m, 1H), 2.80 (m, 2H), 2.93-3.01(m, 2H), 3.28 (m, 2H), 4.20 (d, 1H), 4.60 (m, 1H), 4.86 (m, 1H),6.45(dd, 1H), 7.18 (d, 1H), 7.40 (d, 2H), 8.27 (d, 2H).

[1059] APCl MS m/z 410 [MH]⁺

EXAMPLE 1048-Chloro-5,6-dimethyl-1-(1-pyrimidin-2-yl-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene

[1060]

[1061] Trifluoroacetic acid (0.5 ml) was added to a solution of thecompound from preparation 64 (0.9 g, 2.10 mmol) in toluene (10 ml), andthe reaction mixture was stirred at 100° C. for 18 hours. The cooledmixture was washed with sodium bicarbonate solution and brine thenevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel using dichloromethane:methanol (95:5) aseluant, to afford the title compound as a white foam (530 mg).

[1062]¹H NMR (400 MHz, C₂D₂Cl₄, at 373K): δ 1.23 (d, 3H), 1.82 (m, 2H),2.03 (m, 2H), 2.40 (s, 3H), 3.01-3.19 (m, 3H), 3.29 (m, 1H), 3.49 (m,1H), 3.63 (m, 1H), 4.64 (m, 1H), 4.78 (m, 1H), 6.42 (m, 1H), 7.24 (d,1H), 7.50 (m, 2H), 8.26 (d, 2H).

[1063] APCl MS m/z 432 [MNa]⁺

EXAMPLE 1051-(3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-8-trifluoromethyl-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulene

[1064]

[1065] Sodium hydride (81 mg, 60% dispersion in mineral oil, 2.03 mmol)was added to an ice-cooled solution of 2-amino-5-trifluoromethylphenylmethanol (WO 99/05147, p g 60) (350 mg, 1.8 mmol) in tetrahydrofuran (20ml), and the solution was stirred at 0° C. for 30 minutes. A solution ofthe chloride from preparation 5 (560 mg, 2.0 mmol) in tetrahydrofuran(10 ml) was added dropwise, and once addition was complete the reactionmixture was stirred at room temperature for 5 hours. The reactionmixture was quenched with water (2 ml) and the mixture was partitionedbetween dichloromethane and sodium bicarbonate solution. The layers wereseparated, the organic phase was dried over magnesium sulphate andevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel using dichloromethane:methanol:0.88ammonia (95:5:0.5) as eluant, to afford a white solid (560 mg). Amixture of this solid in xylene (20 ml) and p-toluene sulphonic acid (40mg) was stirred at 140° C. for 18 hours. The cooled solution wasevaporated under reduced pressure and the residue was purified by columnchromatography on silica gel using ethyl acetate:methanol:0.88 ammonia(97:3:0.3 to 90:10:1) as eluant, to afford the title compound as a paleyellow solid (210 mg).

[1066]¹H NMR (400 MHz, MeOD): δ 1.98 (m, 4H), 2.98 (m, 2H), 3.41 (m,1H), 4.37 (m, 2H), 4.57 (s, 2H), 4.61 (s, 2H), 6.64 (m, 1H), 6.63 (d,1H), 7.58 (m, 1H), 7.98 (d, 1H), 8.03 (m, 3H).

[1067] APCl MS m/z 416 [MH]⁺

EXAMPLE 10610-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-6,7-dihydro-4H-5,8-dioxa-2,3,12b-triaza-benzo[a]cyclopenta[c]cyclononene

[1068]

[1069] A mixture of the compound from preparation 61 (250 mg, 0.58 mmol)and p-toluenesulphonic acid (cat) in xylene (75 ml) was stirred at 140°C. for 24 hours. The cooled mixture was concentrated under reducedpressure and the residue was purified by column chromatography on silicagel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant,and purified again using ethyl acetate:methanol:0.88 ammonia (95:5:0.5to 90:10:1) as eluant, to afford the title compound as an off-white foam(42 mg).

[1070]¹H NMR (400 MHz, MeOD): δ 1.30 (m, 2H), 2.04 (m, 2H), 2.74-2.98(m, 3H), 3.70 (m, 1H), 3.81 (m, 1H), 4.19 (m, 3H), 4.37 (m, 1H), 4.50(m, 1H), 4.78 (m, 1H), 6.62 (m, 1H), 6.82 (d, 1H), 7.36 (m, 1H), 7.48(m, 2H), 7.58 (m, 1H), 8.02 (m, 1H).

[1071] APCl MS m/z 412 [MH]⁺

EXAMPLE 1078-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-5-thia-2,3,10b-triaza-benzo[e]azulene

[1072]

[1073] To a solution of the thioamide of preparation 87 (581 mg, 2.53mmol) in butan-1-ol (20 ml) was added the hydrazide of preparation 1(557 mg, 2.53 mmol), and the mixture was heated to 100° C. for 20 hours.The reaction mixture was evaporated under reduced pressure and theresidue was purified by column chromatography on silica gel usingdichloromethane: Methanol (95:5) as eluant, to afford the title compoundas an off-white foam (825 mg)

[1074]¹H NMR (400 MHz, CDCl₃): δ 1.60 (m, 1H), 1.65 (m, 1H), 2.20 (m,1H), 2.40 (m, 1H), 2.80 (m, 1H), 3.00 (m, 2H), 3.40 (d, 1H), 3.60 (m,2H), 4.00 (d, 1H), 4.20 (d, 1H), 4.40 (d, 1H), 6.60 (dd, 1H), 6.65 (d,1H), 7.25 (d, 1H), 7.45 (m, 3H), 8.20 (d, 1H)

[1075] APCl MS m/z 398 [MH]⁺

EXAMPLE 108 8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-5-thia-2,3,10b-triaza-benzo[e]azulene 5-oxide

[1076]

[1077] To a solution of the sulphide of example 107 (150 mg, 0.38 mmol)in 1,1,1,3,3,3-Hexafluoro-propan-2-ol (5 ml) was added a 30% aqueoussolution of hydrogen peroxide (0.09 ml). The resulting reaction mixturewas stirred at room temperature for 1 hour before partitioning withaqueous sodium sulfite. The organic layer was washed with brine, dried(MgSO₄), filtered and evaporated. The resulting residue was purified bycolumn chromatography on silica gel using dichloromethane: Methanol:0.880 ammonia (95:5:0.5) as eluant, to afford the title compound as anoff-white foam (64 mg)

[1078]¹H NMR (400 MHz, CDCl₃): δ 1.55 (m, 1H), 1.75 (m, 1H), 2.20 (m,1H), 2.30 (m, 1H), 2.82 (m, 1H), 3.03 (m, 2H), 3.18 (d, 1H) 3.28 (d,1H), 3.90 (d, 1H), 4.22 (m, 1H), 4.42 (m, 1H), 5.02 (d, 1H), 6.60 (dd,1H), 6.65 (d, 1H), 7.40 (d, 1H), 7.45 (t, 1H), 7.60 (m, 2H), 8.18(d, 1H)

[1079] APCl MS m/z 436 [MH]⁺

EXAMPLE 1098-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-5-thia-2,3,10b-triaza-benzo[e]azulene5,5-dioxide

[1080]

[1081] To a solution of the sulphide of example 107 (150 mg, 0.38 mmol)in 1,1,1-trifluroacetic acid (5 ml) was added a 30% aqueous solution ofhydrogen peroxide (0.09 ml). The resulting reaction mixture was stirredat room temperature for 1 hour before it was diluted with aqueous sodiumhydrogen carbonate solution and extracted with ethyl acetate (2×50 ml).The organic layer was washed with brine, dried (MgSO₄), filtered andevaporated, to afford the title compound as an off-white solid (108 mg)

[1082]¹H NMR (400 MHz, CDCl₃): δ 1.80 (m, 1H), 2.20 (m, 1H), 2.30 (m,1H), 2.82 (m, 1H), 3.03 (m, 2H), 3.95 (d, 1H), 4.10 (m, 2H), 4.25 (m,1H), 4.40 (m, 1H), 4.80 (dd, 1H), 6.65 (m, 2H), 7.405 (m, 2H), 7.70 (m,2H), 8.20 (d, 1H)

[1083] APCl MS m/z 452 [MH]⁺

EXAMPLE 110

[1084] Examples of specific compounds, tested in screen 1.0 (V_(1A)filter binding assay) as described above, are illustrated in the tablebelow Example No. Ki (nM) 5 4.66 6 2.37 8 2.47 11 0.68 13 13.86 15 4.7124 1.00 27 1.25 38 4.63 59 1.32 73 & 74 6.84 & 6.02 93 2.33 96 0.24 1000.77 102 4.16 103 2.02

1. A compound of formula (I),

or a pharmaceutically acceptable derivative thereof, wherein Vrepresents —(CH₂)_(d)(O)_(e)—, —CO—, or —CH(C₁₋₆ alkyl)-; W is —O—,—S(O)_(a)—, or —N(R¹)— R¹ represents H, C₁₋₆ alkyl, (CH₂)_(b)COR²,CO(CH₂)_(b)NR²R³, SO₂R², (CH₂)_(c)OR², (CH₂)_(c)NR²R³, or (CH₂)_(b)het¹;het¹ represents a saturated or unsaturated heterocycle of from 3 to 8atoms containing one or more heteroatoms selected from O, N, or S,optionally substituted with C₁₋₆ alkyl; X and Y independently representH, C₁₋₆ alkyl, halogen, OH, CF₃, OCF₃, OR⁴; Z represents—(CH₂)_(f)(O)_(g)—, —CO—or —CH(C₁₋₆ alkyl)-; Ring A represents a 4-7membered, saturated N-containing heterocycle, optionally substitutedwith OH, and in which optionally at least one ring N is substituted withO; Ring B represents phenyl or a 4-7 membered unsaturated N-containingheterocycle, optionally substituted with OH, halogen, CN, CONH₂, CF₃,OCF₃, and in which optionally at least one ring N is substituted with O;R² and R³ independently represent H, C₁₋₆ alkyl [optionally substitutedwith OH, halogen, N(C₁₋₆ alkyl)₂, or C₁₋₆ alkyloxy], C₁₋₆ alkyloxy,N(C₁₋₆ alkyl)₂, or [C₃₋₈ cycloalkyl]; or R² and R³, together with thenitrogen atom to which they are attached independently represent aheterocycle of from 3 to 8 atoms, optionally substituted with C₁₋₆alkyl; R⁴ represents straight or branched C₁₋₆ alkyl, a and cindependently represent 0, 1, or 2; b, e and g independently represent 0or 1; and d and f independently represent 1 or
 2. 2. A compoundaccording to claim 1, wherein W represents NR¹.
 3. A compound accordingto claim 1, wherein R¹ represents H, C₁₋₆ alkyl, —(CH₂)_(b)COR² orSO₂R².
 4. A compound according to claim 1, wherein R¹ is methyl.
 5. Acompound according to claim 1, wherein R² is morpholinyl or pyrimidinyl(optionally substituted with C₁₋₆ alkyl [optionally substituted with OH,halogen, N(C₁₋₆ alkyl)₂, or C₁₋₆ alkyloxy] or NMe₂).
 6. A compoundaccording to claim 1, wherein X is H.
 7. A compound according to claim1, wherein Y is in the 4-position of the phenylene ring (according tothe numbering of formula (I)) to which it is attached.
 8. A compoundaccording to claim 7, wherein Y is chloro.
 9. A compound according toclaim 1, wherein ring A is linked to ring B via a nitrogen atom in ringA.
 10. A compound according to claim 1, wherein ring A representspiperidinyl (optionally substituted with OH, and optionally at least oneN is substituted with O).
 11. A compound according to claim 1, whereinring B represents pyridinyl or pyrimidinyl (optionally substituted withOH, halogen, CN, CONH₂, CF₃, OCF₃, and optionally at least one ring N issubstituted with O).
 12. A compound according to claim 11, wherein ringB represents pyridinyl.
 13. A compound according to claim 1, wherein Vrepresents —CH₂—.
 14. A compound according to claim 1, wherein Zrepresents —CH₂—.
 15. A compound according to claim 1, wherein when R²and R³ together with the nitrogen to which they are attached represent aheterocycle, the heterocycle is selected from piperazinyl, pyrrolidinyl,piperidinyl, pyrimidinyl, tetrahydropyranyl, or morpholinyl, optionallysubstituted with C₁₋₆ alkyl.
 16. A compound according to claim 1,selected from:8-chloro-5-methyl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulenetrihydrochloride;8-chloro-5-isopropyl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulenetrihydrochloride;1-[8-chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-ethanonedihydrochloride;8-chloro-5-methanesulfonyl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene;8-chloro-5-methyl-1-(1-pyrimidin-2-yl-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene;8-chloro-5-methanesulfonyl-1-(1-pyrimidin-2-yl-piperidin-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene;13-chloro-8-methyl-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-2,4,5,8-tetraaza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),3,5,12,14-pentaene;13-chloro-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-8-oxa-2,4,5-triaza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),3,5,12,14-pentaene;1-[8-chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-2-dimethylamino-ethanone;[8-chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-morpholin-4-yl-methanone;(+) or (−)8-chloro-5-(4-methyl-morpholin-2-ylmethyl)-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene;8-chloro-5-pyrimidin-2-yl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene;8-chloro-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-sulphonic acid dimethylamide;8-chloro-1-(1-pyrimidin-2-yl-piperidin-4-yl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-sulphonic acid dimethylamide;13-chloro-9-methyl-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-2,4,5,9-tetraaza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),3,5,12,14-pentaene;13-chloro-8-methyl-3-(1-pyrimidin-2-yl-piperidin-4-yl)-2,4,5,8-tetraaza-tricyclo[9.4.0.0*2,6*]pentadeca-1(11),3,5,12,14-pentaene;or pharmaceutically acceptable derivatives thereof.
 17. A method oftreatment of anxiety, cardiovascular disease (including angina,atherosclerosis, hypertension, heart failure, edema, hypernatremia),dysmenorrhoea (primary and secondary), endometriosis, emesis (includingmotion sickness), intrauterine growth retardation, inflammation(including rheumatoid arthritis), mittlesmerchz, preclampsia, prematureejaculation, premature (preterm) labor or Raynaud's disease, comprisingadministering a therapeutically effective amount of a compound accordingto claim 1 to a patient suffering from such a disorder.
 18. A methodaccording to claim 17, wherein the disorder is dysmenorrhoea (primary orsecondary).
 19. A pharmaceutical formulation comprising a compoundaccording to claim 1, together with a pharmaceutically acceptableexcipient, diluent or carrier.
 20. The compounds of formulae (II),(III), (X), (XV), (XXIV) and (XXV):

wherein W, X, Y, Z, rings A and B, and n are as defined in claim 1 andLG represents a leaving group.
 21. A process of making a compound offormula (I) as defined in claim 1, or a pharmaceutically acceptablederivative thereof, comprising: reacting a compound of formula (II) withan acid catalyst

wherein rings A and B, and groups W, X, Y and n are as defined above.22. A process of making a compound of formula (I) as defined in claim 1,or a pharmaceutically acceptable derivative thereof, comprising:reacting a compound of formula (III)

with a compound of formula (IV)

wherein rings A and B, and groups W, X, Y and n are as defined in claim1, and Z′ represents a leaving group such as halogen.
 23. A process formaking a compound of formula (I) as defined in claim 1, wherein Wrepresents NR¹, or a pharmaceutically acceptable derivative thereof,comprising: reacting a compound of formula (V)

with a compound of formula (VI)

wherein rings A and B, and groups R¹, X, Y and n are as defined in claim1, and Z″ represents a leaving group such as halogen.
 24. A process formaking a compound of formula (I) as defined in claim 1, wherein Wrepresents NR¹, or a pharmaceutically acceptable derivative thereof,comprising: reacting a compound of formula (V)

with a compound of formula (VII)

wherein rings A and B, and groups R¹, X, Y and n are as defined inclaim
 1. 25. A process for making a compound of formula (I) as definedin claim 1, or a pharmaceutically acceptable derivative thereof,comprising reacting a compound of formula (XIII)

with a compound of formula (XXIV)

wherein rings A and B, and groups V, W, X, Y and Z are as defined inclaim
 1. 26. A process of making a compound of formula (I) as defined inclaim 1, or a pharmaceutically acceptable derivative thereof, comprisingreacting a compound of formula (XIII)

with a compound of formula (XXV)

wherein rings A and B, and groups V, W, X, Y and Z are as defined inclaim 1.